ORCID Profile
0000-0002-5028-3489
Current Organisations
University of Melbourne at The Doherty Institute
,
St. Jude Children's Research Hospital
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Publisher: Elsevier BV
Date: 10-1972
Publisher: Microbiology Society
Date: 02-2003
Abstract: The murine gammaherpesvirus-68 kills I-A(b-/-) mice despite the presence of virus-specific CD8+ cytotoxic T lymphocytes (CTL). This has raised the possibility that these CTL are functionally abnormal. Here, no difference was observed between I-A(b-/-) mice and I-A(b+/+) controls in virus-specific CTL function, T cell receptor usage, or surface phenotype. Thus CTL immunity was independent of CD4+ T cells in a chronic herpesvirus infection, but was still inadequate to control virus replication.
Publisher: The American Association of Immunologists
Date: 07-2011
Publisher: Springer Science and Business Media LLC
Date: 07-1975
DOI: 10.1038/256050A0
Publisher: Elsevier BV
Date: 04-1993
Publisher: Wiley
Date: 30-10-2006
Abstract: Activation of mature CD8+ T cells requires recognition, via the T cell receptor (TCR), of peptide + MHC (pMHC) complexes with an avidity that exceeds a designated threshold. Multiple indicators of T cell avidity have been described that provide unique information on the characteristics of T cell interactions. However, these indicators are routinely used in isolation, and, consequently, little is known about correlations between these measures or which measure, if any, correlates with the quality of the T cell response. Following influenza virus infection of C57BL/6J mice, we analyzed the relative avidities of five epitope-specific CD8+ T cell populations using five different measures. We demonstrated that the quality of CD8+ T cell responses, in terms of cytokine profiles, correlates with TCR dissociation rate and CD8 dependence, but not with the sensitivity to tetramer binding or peptide stimulation. Thus, we propose that, despite significant differences in TCR dissociation rate, the stimulation threshold of influenza-specific CD8+ T cell populations may be equivalent due to compensatory mechanisms largely provided by the CD8 coreceptor. Furthermore, this study shows that different indicators of avidity do not necessarily provide similar information and should be used in combination to obtain an overall picture of the characteristics of TCR binding.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-04-2001
Abstract: The spectrum of immunogenic epitopes presented by the H2-IA b MHC class II molecule to CD4 + T cells has been defined for two different (clade B and clade D) HIV envelope (gp140) glycoproteins. Hybridoma T cell lines were generated from mice immunized by a sequential prime and boost regime with DNA, recombinant vaccinia viruses, and protein. The epitopes recognized by reactive T cell hybridomas then were characterized with overlapping peptides synthesized to span the entire gp140 sequence. Evidence of clonality also was assessed with antibodies to T cell receptor Vα and Vβ chains. A total of 80 unique clonotypes were characterized from six in idual mice. Immunogenic peptides were identified within only four regions of the HIV envelope. These epitope hotspots comprised relatively short sequences (≈20–80 aa in length) that were generally bordered by regions of heavy glycosylation. Analysis in the context of the gp120 crystal structure showed a pattern of uniform distribution to exposed, nonhelical strands of the protein. A likely explanation is that the physical location of the peptide within the native protein leads to differential antigen processing and consequent epitope selection.
Publisher: Elsevier BV
Date: 10-1994
Abstract: Antibody production profiles have been compared for Sendai virus infection of normal mice and mice that lack CD8+ T cells as a consequence of treatment with a lymphocyte subset-specific monoclonal antibody or homozygous disruption of the beta 2-microglobulin (beta 2-m(-/-)) gene encoding the light chain of the class I major histocompatibility complex glycoprotein. Using the single-cell ELISPOT assay, we show a relative increase in IgA antibody forming cell (AFC) numbers in the mediastinal lymph node (MLN), spleen, and bone marrow of the CD8-depleted mice. This is reflected in higher serum IgA titers. Similarly, secondary infection with a large dose of Sendai virus leads to greater prevalence of virus-specific IgA AFCs as early as Day 5 postinfection in the beta 2-m(-/-) mice. Also, in primed beta 2-m(-/-) mice challenged with vaccinia constructs containing the genes for the hemagglutinin-neuraminidase (HN), nuclear protein, or the fusion protein of Sendai virus, the majority of the virus-specific AFCs in the MLN are specific for HN and secrete IgA.
Publisher: American Society for Microbiology
Date: 15-12-2000
DOI: 10.1128/JVI.74.24.11690-11696.2000
Abstract: The recall of CD8 + T-cell memory established by infecting H-2 b mice with an H1N1 influenza A virus provided a measure of protection against an extremely virulent H7N7 virus. The numbers of CD8 + effector and memory T cells specific for the shared, immunodominant D b NP 366 epitope were greatly increased subsequent to the H7N7 challenge, and though lung titers remained as high as those in naive controls for 5 days or more, the virus was cleared more rapidly. Expanding the CD8 + memory T-cell pool ( .5 to %) by sequential priming with two different influenza A viruses (H3N2→H1N1) gave much better protection. Though the H7N7 virus initially grew to equivalent titers in the lungs of naive and double-primed mice, the replicative phase was substantially controlled within 3 days. This tertiary H7N7 challenge caused little increase in the magnitude of the CD8 + D b NP 366 + T-cell pool, and only a portion of the memory population in the lymphoid tissue could be shown to proliferate. The great majority of the CD8 + D b NP 366 + set that localized to the infected respiratory tract had, however, cycled at least once, though recent cell ision was shown not to be a prerequisite for T-cell extravasation. The selective induction of CD8 + T-cell memory can thus greatly limit the damage caused by a virulent influenza A virus, with the extent of protection being directly related to the number of available responders. Furthermore, a large pool of CD8 + memory T cells may be only partially utilized to deal with a potentially lethal influenza infection.
Publisher: Elsevier BV
Date: 02-2007
Publisher: Elsevier BV
Date: 11-1994
Abstract: Bronchoalveolar lavage (BAL) populations recovered from mice with secondary influenza pneumonia contain gamma delta T cell receptor (TCR)+NK1.1- lymphocytes and gamma delta TCR-NK1.1+ natural killer (NK) cell populations. Stimulating the CD4-8- component of the BAL with a monoclonal antibody to CD3 epsilon and rIL-2 leads to the emergence of substantial numbers of CD4-8- gamma delta TCR+NK1.1+ and CD4-8- alpha beta TCR+NK1.1+ lymphocytes. The NK1.1+ gamma delta T cells are potent cytotoxic effectors, causing much higher lysis of YAC-1 target cells than the gamma delta TCR+NK1.1- lymphocytes that are present concurrently. CD4+ and CD8+ alpha beta T cells cultured in the same way express little (if any) NK1.1. The possible functional role of NK1.1+ gamma delta T cells is discussed.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-03-2009
Abstract: Respiratory infection with highly pathogenic influenza A viruses is characterized by the exuberant production of cytokines and chemokines and the enhanced recruitment of innate inflammatory cells. Here, we show that challenging mice with virulent influenza A viruses, including currently circulating H5N1 strains, causes the increased selective accumulation of a particular dendritic cell subset, the tipDCs, in the pneumonic airways. These tipDCs are required for the further proliferation of influenza-specific CD8 + T cells in the infected lung, because blocking their recruitment in CCR2 −/− mice decreases the numbers of CD8 + effectors and ultimately compromises virus clearance. However, diminution rather than total elimination of tipDC trafficking by treatment with the peroxisome proliferator-activated receptor-γ agonist pioglitazone moderates the potentially lethal consequences of excessive tipDC recruitment without abrogating CD8 + T cell expansion or compromising virus control. Targeting the tipDCs in this way thus offers possibilities for therapeutic intervention in the face of a catastrophic pandemic.
Publisher: American Society for Microbiology
Date: 12-2002
DOI: 10.1128/JVI.76.23.12388-12393.2002
Abstract: The primary influenza A virus-specific CD8 + -T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A b +/+ and CD4 + -T-cell-deficient I-A b −/− mice. Comparable levels of virus-specific cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4 + subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A b −/− mice. Thus, though the capacity to mediate the CD8 + -T-cell effector function is broadly preserved in the absence of concurrent CD4 + -T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.
Publisher: Wiley
Date: 04-2004
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1007/S10096-003-1075-3
Abstract: A critical goal of HIV vaccine development is the identification of safe and immunogenic vectors. Recombinant vaccinia virus is a highly effective vaccine vector, with demonstrated capacity to protect animals from various viral pathogens, including rabies. Unlike many other candidate vaccine vectors, vast human experience exists with the parenteral smallpox vaccine. However, consideration of recombinant vaccinia virus as a modern vaccine is complicated by the relatively high prevalence of immunocompromised persons compared to such prevalence 4 or more decades ago (when smallpox vaccination was still routine). Administering vaccine by the subcutaneous (SQ) route, rather than the traditional scarification route, could address these concerns. SQ administration could prevent transmission of vaccinia virus to potentially vulnerable persons it could also avoid the most common adverse events, which are cutaneous in nature. However, previous studies suggest that elicitation of immune response against passenger gene products following SQ administration requires development of a superficial pox lesion, defeating the intention of SQ administration. This is the first report to demonstrate that SQ administration of recombinant vaccinia virus does elicit immune response to the passenger protein in the absence of a cutaneous pox lesion. Results further show that a multi-envelope HIV vaccine can elicit antibody responses toward heterologous HIV-1 not represented by primary sequence in the vaccine. These findings have global implications because they support the consideration of recombinant vaccinia virus as a valuable HIV vaccine vector system.
Publisher: Elsevier BV
Date: 10-1971
Publisher: Wiley
Date: 10-05-2011
DOI: 10.1038/ICB.2011.36
Abstract: The emergence of the novel reassortant A(H1N1)-2009 influenza virus highlighted the threat to the global population posed by an influenza pandemic. Pre-existing CD8(+) T-cell immunity targeting conserved epitopes provides immune protection against newly emerging strains of influenza virus, when minimal antibody immunity exists. However, the occurrence of mutations within T-cell antigenic peptides that enable the virus to evade T-cell recognition constitutes a substantial issue for virus control and vaccine design. Recent evidence suggests that it might be feasible to elicit CD8(+) T-cell memory pools to common virus mutants by pre-emptive vaccination. However, there is a need for a greater understanding of CD8(+) T-cell immunity towards commonly emerging mutants. The present analysis focuses on novel and immunodominant, although of low pMHC-I avidity, CD8(+) T-cell responses directed at the mutant influenza D(b)NP(366) epitope, D(b)NPM6A, following different routes of infection. We used a C57BL/6J model of influenza to dissect the effectiveness of the natural intranasal (i.n.) versus intraperitoneal (i.p.) priming for generating functional CD8(+) T cells towards the D(b)NPM6A epitope. In contrast to comparable CD8(+) T-cell responses directed at the wild-type epitopes, D(b)NP(366) and D(b)PA(224), we found that the priming route greatly affected the numbers, cytokine profiles and TCR repertoire of the responding CD8(+) T cells directed at the D(b)NPM6A viral mutant. As the magnitude, polyfunctionality, and T-cell repertoire ersity are potential determinants of the protective efficacy of CD8(+) T-cell responses, our data have implications for the development of vaccines to combat virus mutants.
Publisher: Elsevier BV
Date: 08-1994
DOI: 10.1016/0952-7915(94)90139-2
Abstract: Recent experiments show that laboratory mice infected once with an influenza A virus or with the murine parainfluenza type 1 virus, called the Sendai virus, have enhanced numbers of cytotoxic T-lymphocyte precursors ( > 20x background) for life. Neither virus persists at the genome level, and the mice are maintained under conditions where there is no possibility of re-infection. These observations are highly relevant to any understanding of CD8+ cell memory and suggest that the clonal burst size associated with the primary challenge is a key determining factor.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-01-2013
Abstract: Ecology is typically thought of as the study of interactions organisms have with each other and their environment and is focused on the distribution and abundance of organisms both within and between environments. On a molecular level, the capacity to probe analogous questions in the field of T-cell immunology is imperative as we acquire substantial datasets both on epitope-specific T-cell populations through high-resolution analyses of T-cell receptor (TCR) use and on global T-cell populations analyzed via high-throughput DNA sequencing. Here, we present the innovative application of existing statistical measures (used typically in the field of ecology), together with unique statistical analyses, to comprehensively assess how the naïve epitope-specific CD8 + cytotoxic T lymphocyte (CTL) repertoire translates to that found following an influenza-virus–specific immune response. Such interrogation of our extensive, cumulated TCR CDR3β sequence datasets, derived from both naïve and immune CD8 + T-cell populations specific for four different influenza-derived epitopes (D b NP 366 , influenza nucleoprotein amino acid residues 366–374 D b PA 224 , influenza acid polymerase amino acid residues 224–233 D b PB1-F2 62 , influenza polymerase B 1 reading frame 2 amino acid residues 62–70 K b NS2 114 , and influenza nonstructural protein 2 amino acid residues 114–121), demonstrates that epitope-specific TCR use in an antiviral immune response is the consequence of a complex interplay between the intrinsic characteristics of the naïve cytotoxic T lymphocyte precursor pool and extrinsic (likely antigen driven) influences, the contribution of which varies in an epitope-specific fashion.
Publisher: Elsevier BV
Date: 10-1988
DOI: 10.1016/0008-8749(88)90246-8
Abstract: The severe inflammation characteristic of the infection of adult mice with murine lymphocytic choriomeningitis virus (LCMV) is induced earlier in unsuppressed, virus-infected recipients by the adoptive transfer of class I MHC-compatible, CD4- CD8+ LCMV-immune spleen cell populations. The time to onset of fatal LCM may also be slightly diminished, though not to the extent that would be expected from the enhanced kinetics of the extravasation of cells into cerebrospinal fluid. The development of symptoms is thus not solely related to the magnitude of the inflammatory process. The majority of the T lymphocytes in the inflammatory exudate are of host origin and have the size characteristics of resting cells, while the minority population of donor T cells show more of a lymphoblast morphology. The findings are consistent with the idea that relatively few CD8+ virus-immune effectors trigger an inflammatory process which consists largely of secondarily recruited host T cells and monocyte/macrophages.
Publisher: American Society for Microbiology
Date: 15-10-2000
DOI: 10.1128/JVI.74.20.9762-9765.2000
Abstract: Optimal expansion of influenza virus nucleoprotein (D b NP 366 )-specific CD8 + T cells following respiratory challenge of naive Ig −/− μMT mice was found to require CD4 + T-cell help, and this effect was also observed in primed animals. Absence of the CD4 + population was consistently correlated with diminished recruitment of virus-specific CD8 + T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8 + set generated during the recall response in Ig −/− mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4 + T-cell response. Both the magnitude and the localization profiles of virus-specific CD8 + T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4 + T cells.
Publisher: Elsevier BV
Date: 03-1983
DOI: 10.1016/0008-8749(83)90383-0
Abstract: Specific and nonspecific T-cell invasion into cerebrospinal fluid has been investigated in the nonfatal viral meningoencephalitis induced by intracerebral inoculation of mice with vaccinia virus. At the peak of the inflammatory process on Day 7 approximately 5 to 10% of the Lyt 2+ T cells present are apparently specific for vaccinia virus. Concurrently, in mice primed previously with influenza virus, 0.5 to 1.0% of the appropriate T-cell set located in cerebrospinal fluid is reactive to influenza-infected target cells. This vaccinia virus-induced inflammatory exudate may thus contain as many as 500 influenza-immune memory T cells. These findings are discussed from the aspect that such nonspecific T-cell invasion into the central nervous system during aseptic viral meningitis could result in exposure of potentially brain-reactive T cells to central nervous system components.
Publisher: Springer Science and Business Media LLC
Date: 09-1986
DOI: 10.1007/BF01940699
Abstract: Throughout the 20th century, US public health and immigration policies intersected with and informed one another in the country's response to Mexican immigration. Three historical episodes illustrate how perceived racial differences influenced disease diagnosis: a 1916 typhus outbreak, the midcentury Bracero Program, and medical deportations that are taking place today. Disease, or just the threat of it, marked Mexicans as foreign, just as much as phenotype, native language, accent, or clothing. A focus on race rendered other factors and structures, such as poor working conditions or structural inequalities in health care, invisible. This attitude had long-term effects on immigration policy, as well as on how Mexicans were received in the United States.
Publisher: Elsevier BV
Date: 09-1993
DOI: 10.1016/0966-842X(93)90133-C
Abstract: To evaluate and compare the buccolingual inclinations of maxillary and mandibular first molars in untreated children and adults. One hundred and thirty-eight subjects were selected and ided into three groups, as follows: (1) age 6-9 years, N = 46 (2) age 10-19 years, N = 56 and (3) age 25-35 years, N = 36. For each subject, existing cone beam computed tomography images were used, and the long axis for each maxillary and mandibular first molar was determined. The converge angles formed by the long axis of left and right maxillary first molars and by the long axis of left and right mandibular first molars were measured. The maxillary molars exhibited buccal inclination, with the converge angle of 21.1° ± 9.5° in group 1, 17.3° ± 8.6° in group 2, and 9.3° ± 7.3° in group 3. Statistically significant differences were found between groups 1 and 3 and groups 2 and 3, but not between groups 1 and 2. The mandibular molars exhibited lingual inclination, with the converge angle of 34.9° ± 11° for group 1, 26.6° ± 9.2° for group 2, and 26.1° ± 7.7° for group 3. Statistically significant differences were found between groups 1 and 2 and groups 1 and 3, but not between groups 2 and 3. Maxillary first molars exhibited buccal inclination. Adults displayed less inclination than did children. Mandibular first molars exhibited lingual inclination. Adults displayed less inclination than did children. Some degree of curve of Wilson should be maintained at the end of orthodontic treatment to fulfill physiologic needs and stability.
Publisher: Wiley
Date: 1995
Abstract: Minimal numbers of CD8+ T cells are found in bronchoalveolar lavage (BAL) populations recovered from Sendai virus-infected mice that are homozygous (-/-) for a beta 2-microglobulin (beta 2-m) gene disruption. The prevalence of the CD8+ set was substantially increased in the pneumonic lungs of 8-12-week radiation chimeras made using substantially class I major histocompatibility complex (MHC) glycoprotein-negative beta 2-m (-/-) recipients and normal beta 2-m (+/+) bone marrow. Even so, the CD8+ (but not the CD4+) lymphocyte counts were still much lower than in the (+/+)-->(+/+) controls. The (+/+)-->(+/+) and (+/+)-->(-/-) chimeras cleared Sendai virus and potent virus-immune CD8+ cytotoxic T lymphocytes (CTL) specific for H-2Kb+viral nucleoprotein peptide were found in the BAL from both groups. However, following in vivo depletion of the CD4+ population, only the (+/+)-->(+/+) mice were able to deal with the infection. Similarly, adoptively transferred, H-2Kb-restricted CD8+ T cells from previously-primed (+/+) mice also failed to clear virus from the lungs of (+/+)-->(-/-) chimeras infected within 2 weeks of reconstitution with bone marrow, though they were effective in the (+/+)-->(+/+) controls. Sendai virus-immune CD8+ T cells are thus unable to eliminate virus-infected beta 2-m (-/-) lung epithelial cells that might be thought to be expressing very small amounts of either isolated class I heavy chain, or class I MHC glycoprotein that has bound beta 2-m derived from beta 2-m (+/+) T cells or macrophages present in the pneumonic lung. Furthermore, the CD8+ CTL that are being exposed to beta 2-m (+/+) stimulators in the BAL population cannot operate in some bystander mode to clear virus from respiratory epithelium.
Publisher: Elsevier BV
Date: 1985
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/0008-8749(92)90005-A
Abstract: Acute inflammatory processes are extremely complex, containing sets of activated cells that may be difficult to categorize. The interface between two methodologies for characterizing the involvement of gamma delta T cells, in situ hybridization to detect T cell receptor (TCR) mRNA and flow cytometric analysis of surface TCR expression, is utilized here to study the pneumonia caused by intranasal (i.n.) infection of mice with influenza A viruses. Substantial numbers of cells expressing mRNA for the gamma and delta TCR chains are present in bronchoalveolar lavage (BAL) populations obtained either late in the course of primary infection with an H3N2 virus or within a few days of secondary challenge with an H1N1 virus. The majority of the gamma delta TCR mRNA+ cells detected in FACS-separated BAL populations partition to the Thy1+ gamma delta TCR+ subset, while relatively few (less than 10%) C delta mRNA transcripts are found in cells that phagocytose latex particles. However, an additional set of gamma delta TCR mRNA+ cells is also located in a high side scatter (H-SSC) population, which stains nonspecifically with monoclonal antibodies (mAbs) and is normally gated out in the process of flow cytometric analysis. This H-SSC population tends to be enriched for cells expressing C gamma 1/2 rather than C gamma 4 mRNA. While some gamma delta TCR+ lymphocytes can be demonstrated by in vitro stimulation of the CD3 epsilon+ subset within this H-SSC population, the majority of the gamma delta T cell precursors that can be expanded in culture demonstrate a low side scatter (L-SSC) profile more characteristic of normal T lymphocytes. The possibility that subsets of activated, granular (H-SSC) alpha beta TCR+ and C gamma 1/2 mRNA+ gamma delta T cells are being missed when conventional FACS analysis is used to study this viral pneumonia is discussed.
Publisher: The American Association of Immunologists
Date: 05-2014
Abstract: Virus-specific CTL responses typically fall into reproducible hierarchies with particular epitopes eliciting either immunodominant or subdominant responses after viral challenge. The recently acquired capacity to directly enumerate naive CTL precursors (CTLps) in both mice and humans has implicated CTLp frequency as a key predictor of immune response magnitude after Ag challenge. However, recent studies have indicated that naive CTLp frequencies do not necessarily predict the size of the Ag-driven response, indicating an important role for differential CTLp recruitment and/or expansion. This study characterizes the early emergence of various influenza epitope-specific CTL responses at multiple sites in C57BL/6 mice, and probes the role of Ag dose and TCR avidity in dictating immune response hierarchies. Despite large naive CTLp numbers, subdominance was found to arise largely as a consequence of the abrupt and premature cessation of CTL proliferation, at least for one epitope specificity. Investigation into the possible drivers of the poor proliferation observed for subdominant specificities showed that the immunodominance hierarchy endured irrespective of epitope abundance, and correlated with the prevalence of high-avidity T cells in both the naive and immune compartments. Our study strongly indicates that the quality, and not simply the quantity, of antiviral CTLs dictate response magnitude.
Publisher: Rockefeller University Press
Date: 08-1976
Abstract: Lymphocytic choriomeningitis virus (LCMV) and ectromelia virus-specific T-cell-mediated cytotoxicity was assayed in various strain combinations using as targets peritoneal macrophages which have been shown to express Ia antigens. Virus-specific cytotoxicity was found only in H-2K- or D-region compatible combinations. I-region compatibility was not necessary nor alone sufficient for lysis. Six different I-region specificities had no obvious effect on the capacity to generate in vivo specific cytotoxicity (expressed in vitro) associated with Dd. Low LCMV-specific cytotoxic activity generated in DBA/2 mice was caused by the non-H-2 genetic background. This trait was inversely related to the infectious virus dose and recessive. Non-H-2 genes, possibly involved in controlling initial spread and multiplication of virus, seem to be, at least in the ex les tested, more important in determining virus-specific cytotoxic T-cell activity in spleens than are Ir genes coded in H-2.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-07-1999
Abstract: The virus-specific CD8 + T cell response has been analyzed through the development, effector, and recovery phases of primary and secondary influenza pneumonia. Apparently, most, if not all, memory T cells expressing clonotypic receptors that bind a tetrameric complex of influenza nucleoprotein (NP) 366–374 peptide+H-2D b (NPP) are induced to ide during the course of this localized respiratory infection. The replicative phase of the recall response ends about the time that virus can no longer be recovered from the lung, whereas some primary CD8 + NPP + T cells may proliferate for a few more days. The greatly expanded population of CD8 + NPP + memory T cells in the lymphoid tissue of secondarily challenged mice declines progressively in mean prevalence over the ensuing 100 days, despite the fact that at least some of these lymphocytes continue to cycle. The recall of cell-mediated immunity thus is characterized by massive proliferation of the antigen-specific CD8 + set, whereas the extent of lymphocyte turnover in the absence of cognate peptide is variable, at a low level, and can be influenced by intercurrent infection.
Publisher: Springer Science and Business Media LLC
Date: 12-1986
DOI: 10.1007/BF00377960
Abstract: Hemangiomas are benign vascular tumors associated with proliferation of blood vessels in bone or soft tissue and they are usually incidental findings in vertebrae. When symptomatic, they present with features of radiculopathy, myelopathy, or vertebral fractures. Treatment options are varied, include sole embolization, embolization combined with surgical excision, surgical excision alone, percutaneous ablation, and radiotherapy. We hereby describe a series of seven cases of symptomatic vertebral hemangiomas operated from 2006 to 2009. Their clinical and radiological profile and outcome have been described. All patients were subjected to surgical excision followed by instrumentation. Outcome was assessed at a followup of 2 years following surgery with Frankel grading system. Seven patients (five females and two males) were included in the study. The mean age was 33.85 years with the mean duration of symptoms of 12 months. All seven cases were symptomatic vertebral hemangiomas with cord compression and underwent surgical excision. Preoperatively, patients with poor Frankel grade such as A and B improved postoperatively to C, D, or E. Surgical excision of these lesions is difficult due to the tremendous amount of intraoperative bleeding. During surgery, brisk bleeding is usually encountered, but can be brought under control with adequate preoperative preparation and expertize. Preoperative embolization may help to reduce the bleeding, but at times it may be difficult to do if vertebrae are replaced by a solid hard mass. In spite of the risks associated with surgery, it still is the treatment of choice as a single intervention, especially in aggressive vertebral hemangiomas.
Publisher: Birkhäuser Basel
Date: 2008
Publisher: Elsevier BV
Date: 12-1997
Abstract: The immune system has evolved to deal with pathogens. Analysing what happens during the course of infectious processes provides insights into the limits of lymphocyte homeostasis. Virus infections greatly alter normal T- and B-cell prevalence and localization patterns. Any mechanism that 'counts' T cells and B cells seems to be disrupted, at least while antigen persists. There is no simple 'dumping' process that controls numbers in the blood. Though the cell-surface 'language' that determines lymphocyte trafficking patterns must be central to modulating the consequences of infectious diseases, it is far from clear how such interactions maintain the system in reasonable balance.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2005
DOI: 10.1038/NI1175
Abstract: Using both 'reverse genetics' and structural analysis, we have examined the in vivo relationship between antigenicity and T cell receptor (TCR) repertoire ersity. Influenza A virus infection of C57BL/6 mice induces profoundly different TCR repertoires specific for the nucleoprotein peptide of amino acids 366-374 (NP366) and the acid polymerase peptide of amino acids 224-233 (PA224) presented by H-2D(b). Here we show the H-2D(b)-NP366 complex with a 'featureless' structure selected a limited TCR repertoire characterized by 'public' TCR usage. In contrast, the prominent H-2D(b)-PA224 complex selected erse, in idually 'private' TCR repertoires. Substitution of the arginine at position 7 of PA224 with an alanine reduced the accessible side chains of the epitope. Infection with an engineered virus containing a mutation at the site encoding the exposed arginine at position 7 of PA224 selected a restricted TCR repertoire similar in ersity to that of the H-2D(b)-NP366-specific response. Thus, the lack of prominent features in an antigenic complex of peptide and major histocompatibility complex class I is associated with a diminished spectrum of TCR usage.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2010
DOI: 10.1007/S00441-010-1043-Z
Abstract: Infection by influenza virus leads to respiratory failure characterized by acute lung injury associated with alveolar edema, necrotizing bronchiolitis, and excessive bleeding. Severe reactions to infection that lead to hospitalizations and/or death are frequently attributed to an exuberant host response, with excessive inflammation and damage to the epithelial cells that mediate respiratory gas exchange. The respiratory mucosa serves as a physical and chemical barrier to infection, producing mucus and surfactants, anti-viral mediators, and inflammatory cytokines. The airway epithelial cell layer also serves as the first and overwhelmingly primary target for virus infection and growth. This review details immune events during influenza infection from the viewpoint of the epithelial cells, secretory host defense mechanisms, cell death, and recovery.
Publisher: Elsevier BV
Date: 02-1989
DOI: 10.1016/0008-8749(89)90395-X
Abstract: The thymus of chimeras made using T cell-depleted donor bone marrow from Thy1.1+ mice and 950 rad Thy 1.2+ recipients is dominated initially by cells expressing the Thy 1.2+ phenotype of the irradiated host. The thymocyte population recovered at 2 weeks after reconstitution comprises 80% Thy 1.2+ cells (host), the remainder being Thy 1.1+ (donor). This situation is normally reversed within a further week, with the host Ty 1.2+ (donor). This situation is normally reversed within a further week, with the host Thy 1.2+ thymocytes being present at a frequency of less than 5% from Week 4. Infection with lymphocytic choriomeningitis virus (LCMV) at 1 week after reconstitution with bone marrow causes a profound and persistent drop in the total number of thymocytes. The decline is equivalent for all categories of donor-derived thymocytes defined by two-color flow microfluorometric analysis for CD4 and CD8. However, there is a partial compensation by the retention of cells originating from the Thy 1.2+ host, which constitute 30-40% of the total thymocyte pool as late as 8 weeks after administration of bone marrow in the LCMV-infected chimeras. These radiation-resistant precursors give rise to CD4-8-, CD4-8+, CD4+8-, and CD4+8+ thymocytes, with the latter category being present at increased frequency. The potential skewing of the mature T cell repertoire as a consequence of persistent virus infection is discussed.
Publisher: Elsevier BV
Date: 10-1994
DOI: 10.1016/1074-7613(94)90043-4
Abstract: MHC class I molecules present peptides generated by processing of endogenously synthesized proteins to CD8+ T lymphocytes. Recently, large proteolytic complexes, termed proteasomes, were implicated in antigen processing. Two proteasomal subunits, LMP2 and LMP7, are encoded within the MHC class II region, but their precise role in antigen processing is unknown. We have generated mice that harbor a disruption in their LMP2 gene. Proteasomes purified from spleen and liver of these mutant mice exhibit altered peptidase activities, and antigen-presenting cells showed reduced capacity to stimulate a T cell hybridoma specific for H-2Db plus a nucleoprotein epitope of an influenza A virus. The mutant mice have reduced (60%-70% of wild type) levels of CD8+ T lymphocytes and generate 5- to 6-fold fewer influenza nucleoprotein-specific cytotoxic T lymphocyte precursors. These findings indicate that LMP2 influences antigen processing.
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0167-5699(90)90020-A
Abstract: Considerable interest has arisen over the past few years in a clinical syndrome characterized by a tendency to arterial or venous thrombosis, and the presence in the serum of antibodies to anionic phospholipids. In this article, Charles Mackworth-Young reviews the clinical features of this so-called 'anti-phospholipid syndrome', the characteristics of the anti-phospholipid response and the evidence for a possible role for these antibodies in pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 12-1976
DOI: 10.1007/BF01576981
Publisher: Elsevier BV
Date: 05-1981
DOI: 10.1016/0008-8749(81)90276-8
Abstract: Ascertain the association of elevated co-occurring anxiety and depression symptoms, elevated anxiety symptoms alone or elevated depression symptoms alone with indicators of self-care behaviours in people with type 2 diabetes. Data from a community s le of 1,990 people diagnosed with type 2 diabetes for less than 10 years were assessed. All participants took part in a telephone interview. Questionnaires examined depression, anxiety, health, and indicators of self-care (physical activity, blood glucose monitoring, diet and smoking). Data were assessed with cross tabulations, ANOVA and logistic regression. Groups who met criteria for elevated co-occurring anxiety and depression symptoms, elevated anxiety symptoms and elevated depression symptoms were more likely to report poor eating habits. Meeting criteria for either elevated depression symptoms (with and without anxiety) was also associated with an increased likelihood of not meeting physical activity recommendations. Those people with elevated depression and anxiety scores were more likely to be a current smoker. Those people who meet criteria for elevated anxiety and/or depression symptoms are less likely to report adhering to self-care recommendations. These associations are particularly marked in those people with elevated depression symptoms with or without co-occurring anxiety symptoms. There is a lot of evidence emphasising the importance of monitoring depressive symptoms in people with diabetes. Our results add to this, indicating that adherence to self-care recommendations should be carefully monitored in people with depression and anxiety symptoms.
Publisher: Public Library of Science (PLoS)
Date: 20-09-2013
Publisher: The American Association of Immunologists
Date: 08-01-2010
Abstract: Naive and recall CD4+ T cell responses were probed with recombinant influenza A viruses incorporating the OVA OT-II peptide. The extent of OT-II–specific CD4+ T cell expansion was greater following primary exposure, with secondary challenge achieving no significant increase in numbers, despite higher precursor frequencies. Adoptive transfer experiments with OT-II TCR-transgenic T cells established that the predominant memory set is CD62Lhi, whereas the CD62Llo precursors make little contribution to the recall response. Unlike the situation described by other investigators, in which the transfer of very large numbers of in vitro-activated CD4 effectors can modify the disease process, providing CD62Lhi or CD62Llo OT-II–specific T cells at physiological levels neither enhanced virus clearance nor altered clinical progression. Some confounding effects of the transgenic model were observed, with decreasing primary expansion efficiency correlating with greater numbers of transferred cells. This was associated with increased levels of mRNA for the proapoptotic molecule Bim in cells recovered following high-dose transfer. However, even with very low numbers of transferred cells, memory T cells did not expand significantly following secondary challenge. A similar result was recorded in mice primed and boosted to respond to an endogenous IAb-restricted epitope derived from the influenza virus hemagglutinin glycoprotein. Depletion of CD8+ T cells during secondary challenge generated an increased accumulation of OT-II–specific T cells but only at the site of infection. Taken together, significant expansion was not a feature of these secondary influenza-specific CD4 T cell responses and the recall of memory did not enhance recovery.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-01-2014
Abstract: Exactly how memory cells are selected into a recall response to acute viral infection (stochastic or deterministic) remains unresolved. This paper demonstrates definitively that selection of virus-specific CD8 + T cells from memory occurs via active selection of particular T-cell clones after secondary virus infection and that this selection appears to be based on the avidity of the T-cell receptor (TCR) for the virus-derived peptide (p) + major histocompatibility complex class I molecule. We also show that despite clear clonal preferences, there is no global narrowing of epitope-specific TCR ersity in the recall response. We propose that the immune system has evolved such a strategy to optimize cytotoxic T-lymphocyte responses while safeguarding TCR repertoire ersity.
Publisher: Frontiers Media SA
Date: 2012
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JIM.2010.06.003
Abstract: Use of fluorescently labelled multimers, particularly tetramers of peptide and MHC class I glycoprotein (pMHC-I) complexes, is essential for the analysis of CD8+ T cell immunity in basic research and clinical settings. A recently described combinatorial approach using pMHC-I multimers coupled to a unique combination of distinct fluorochromes has facilitated the simultaneous screening of multiple T cell specificities within a single human blood s le. The present analysis establishes that this multiplexed tetramer staining protocol can also be applied in mouse models of a disease to detect multiple subdominant CD8+ T cell specificities in the presence of prominent immunodominant T cell sets at different stages of infection. We have established a modified protocol that concurrently identified influenza-specific CD8+ T cells at the acute and long-term memory phases of influenza virus infection in B6 mice. Highly dominant (D(b)NP(366)+CD8+ and D(b)PA(224)+CD8+) and subdominant (K(b)PB1(703)+CD8+, D(b)PB1-F2(62)+CD8+ and K(b)NS2(114)+CD8+) T cell responses can be detected simultaneously at levels comparable to the conventional tetramer staining with this combinatorial approach. The technique proved particularly useful with aged mice, where we used 5-fold fewer animals, making the detection of multiple T cell specificities more cost-effective and less time-consuming. Overall, our study establishes that this comprehensive concurrent analysis of multiple T cell specificities is of value for analysing mouse models of disease, especially in situations where s le size and/or response magnitude is limiting.
Publisher: Rockefeller University Press
Date: 29-09-2003
DOI: 10.1084/JEM.20021745
Abstract: Contact-mediated interactions between CD4+ T cells and B cells are considered crucial for T cell–dependent B cell responses. To investigate the ability of activated CD4+ T cells to drive in vivo B cell responses in the absence of key cognate T–B interactions, we constructed radiation bone marrow chimeras in which CD4+ T cells would be activated by wild-type (WT) dendritic cells, but would interact with B cells that lacked expression of either major histocompatibility complex class II (MHC II) or CD40. B cell responses were assessed after influenza virus infection of the respiratory tract, which elicits a vigorous, CD4+ T cell–dependent antibody response in WT mice. The influenza-specific antibody response was strongly reduced in MHC II knockout and CD40 knockout mice. MHC II–deficient and CD40-deficient B cells in the chimera environment also produced little virus-specific immunoglobulin (Ig)M and IgG, but generated a strong virus-specific IgA response with virus-neutralizing activity. The IgA response was entirely influenza specific, in contrast to the IgG2a response, which had a substantial nonvirus-specific component. Our study demonstrates a CD4+ T cell–dependent, antiviral IgA response that is generated in the absence of B cell signaling via MHC II or CD40, and is restricted exclusively to virus-specific B cells.
Publisher: Springer Science and Business Media LLC
Date: 12-1976
DOI: 10.1007/BF01576984
Publisher: Springer Basel
Date: 22-09-2011
Publisher: Bentham Science Publishers Ltd.
Date: 04-2005
Abstract: A central obstacle to the design of a global HIV vaccine is viral ersity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic ersity has been addressed by vaccine design. For ex le, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness erse, envelope-specific B-cell and T-cell responses, are reviewed.
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0952-7915(97)80094-5
Abstract: Limb-preserving surgery in young children suffering malignant bone tumor of the femur is challenging due to the specific anatomical conditions. Extendable tumor endoprostheses are often oversized, while custom-made endoprostheses do not provide the intraoperatively required variability regarding reconstruction length. Allo- and autograft replacements, on the other hand, show high complication and revision rates. We report a novel reconstructive procedure after resection of malignant bone tumors of the femur in young children, and present our preliminary results of this technique.
Publisher: Elsevier BV
Date: 1997
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-01-2010
Abstract: The past decade of research on the immune system has seen an incredible expansion of knowledge in the area of innate immunity. Analysis over the preceding years had focused largely on how T and B cells orchestrate immune responses to specific pathogens, and how their memory of these encounters confers long-lasting protection. In contrast to these specific “adaptive” mechanisms, innate immunity is driven by a plethora of proteins produced by a wide range of cells throughout the body, and it provides immediate broad-spectrum responses to foreign invaders. This new understanding of innate immunity is providing insights into host reactions to noninfectious diseases such as cancer, to antigen-independent inflammatory conditions such as periodic fever syndromes, and to the inflammatory modulation of basic cellular metabolic processes. As this special issue on innate immunity points out (p. 283), ongoing research to further characterize this complex response system has great potential for identifying new therapies to treat human disease.
Publisher: American Society for Clinical Investigation
Date: 06-2010
DOI: 10.1172/JCI41538
Publisher: American Society for Microbiology
Date: 15-11-2007
DOI: 10.1128/JVI.00197-07
Abstract: The importance of antigen-specific CD4 + helper T cells in virus infections is well recognized, but their possible role as direct mediators of virus clearance is less well characterized. Here we describe a recombinant Sendai virus strategy for probing the effector role(s) of CD4 + T cells. Mice were vaccinated with DNA and vaccinia virus recombinant vectors encoding a secreted human immunodeficiency virus type 1 (HIV-1) envelope protein and then challenged with a Sendai virus carrying a homologous HIV-1 envelope gene. The primed mice showed (i) prompt homing of numerous envelope-primed CD4 + T cell populations to the virus-infected lung, (ii) substantial production of gamma interferon, and interleukin-2 (IL-2), IL-4, and IL-5 in that site, and (iii) significantly reduced pulmonary viral load. The challenge experiments were repeated with immunoglobulin −/− μMT mice in the presence or absence of CD8 + and/or CD4 + T cells. These selectively immunodeficient mice were protected by primed CD4 + T cells in the absence of antibody or CD8 + T cells. Together, these results highlight the role of CD4 + T cells as direct effectors in vivo and, because this protocol gives such a potent response, identify an outstanding experimental model for further dissecting CD4 + T-cell-mediated immunity in the lung.
Publisher: Elsevier BV
Date: 10-1973
DOI: 10.1016/0021-9975(73)90006-6
Abstract: The present in vitro study evaluated the secondary caries resistance potential of acid-etched human coronal dentin bonded using augmented pressure adhesive displacement in conjunction with an experimental antibacterial adhesive. One hundred and twenty class I cavities were restored with a commercial non-antibacterial etch-and-rinse adhesive (N) or an experimental antibacterial adhesive (A) which was displaced by gentle air-blow (G) or augmented pressure air-blow (H). After bonding and restoration with resin composite, the resulted 4 groups (N-G, N-H, A-G and A-H) were exposed to Streptococcus mutans biofilm for 4, 8, 15, 20 or 25 days. The development of secondary caries in the bonding interface was then examined by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Data acquired from 15, 20 and 25 days of artificial caries induction were analyzed with three-way ANOVA at α = 0.05. The depth of the artificial carious lesions was significantly affected by "adhesive type" (Single Bond 2 vs experimental antibacterial adhesive p = 0.003), "intensity of adhesive displacement" (gentle vs augmented-pressure adhesive displacement p < 0.001), as well as "artificial caries induction time" (p < 0.001). The combined use of augmented pressure adhesive displacement and experimental antibacterial adhesive reduces the progression of secondary caries.
Publisher: Public Library of Science (PLoS)
Date: 10-02-2015
Publisher: American Society for Microbiology
Date: 05-2001
DOI: 10.1128/JVI.75.9.4435-4438.2001
Abstract: The cycling characteristics of CD8 + T cells specific for two lytic-phase epitopes of murine gammaherpesvirus 68 (γHV68) have been analyzed for mice with high or low levels of virus persistence. The extent of cell ision is generally reflective of the antigen load and suggests that γHV68 may be regularly reactivating from latency for some months after the resolution of the acute phase of the infectious process. Although γHV68 infection is also associated with massive proliferation of lymphocytes that are not obviously specific for the virus, the level of “bystander-induced” cycling in a population of influenza virus-specific CD8 + T cells was generally fourfold lower than the extent of cell ision seen for the antigen-driven, γHV68-specific response. The overall conclusion is that turnover rates substantially in excess of 5 to 10% over 6 days for CD8 + “memory” T-cell populations are likely to be reflective of continued antigenic exposure.
Publisher: Elsevier BV
Date: 03-1978
Publisher: Mary Ann Liebert Inc
Date: 02-2005
Abstract: Our previous work has shown that immunodominant T-helper cell epitopes cluster within distinct fragments on a single face of the HIV envelope gp120 protein. We show in this report that the general positions of immunodominant epitopes are shared by T cells derived from BALB/c, C57BL/6, and CB6F1 mice, yet the precise peptides recognized by the responding T cell populations may differ. In addition, we find that gp120 peptides displayed by tryptic digestion and mass spectrometry of a purified HIV envelope protein share location with peptides defined as immunodominant T cell targets. Results are consistent with the suggestion that gp120 peptide location influences antigen processing, which, in turn, influences the specificity of immunodominant T cells.
Publisher: Elsevier BV
Date: 03-1981
DOI: 10.1016/0165-5728(81)90011-4
Abstract: Mice injected intracerebrally (i.c.) with mastocytoma cells reject the tumor, which grows rapidly in cerebrospinal fluid (CSF), within 7 or 8 days. The characteristics of the inflammatory exudate have been examined by several different, functional criteria. Potent cytotoxic T-lymphocyte populations are readily demonstrated in CSF, and both phagocytic and non-phagocytic cells capable of mediating antibody-dependent cell-mediated cytotoxicity are also present. However, no tumor-specific antibody was detected in CSF of mice that had recently rejected the tumor, using sensitive complement-dependent and lymphocyte-dependent cytotoxic assay systems. The process of cell-mediated tumor rejection does not obviously compromise the blood-CSF barrier to immunoglobulins.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-2004
Abstract: Much of the CD8 + T cell response in H2 b mice with influenza pneumonia is directed at the nucleoprotein 366-374 (NP 366 ) and acid polymerase 224-233 (PA 224 ) peptides presented by the H2D b MHC class I glycoprotein. These D b NP 366 - and D b PA 224 -specific T cell populations are readily analyzed by staining with tetrameric complexes of MHC + peptide (tetramers) or by cytokine production subsequent to in vitro stimulation with the cognate peptides. The D b PA 224 -specific CD8 + effector T cells make more tumor necrosis factor (TNF) α than the comparable CD8 + D b NP 366 + set, a difference reflected in the greater sensitivity of the CD8 + D b PA 224 + population to TNF receptor (TNFR) 2-mediated apoptosis under conditions of in vitro culture. Freshly isolated CD8 + D b NP 366 + and CD8 + D b PA 224 + T cells from influenza-infected TNFR2 -/- mice produce higher levels of IFN-γ and TNF-α after in vitro stimulation with peptide, although the avidity of the T cell receptor-epitope interaction does not change. Increased numbers of both CD8 + D b PA 224 + and CD8 + D b NP 366 + T cells were recovered from the lungs (but not the spleens) of secondarily challenged TNFR2 -/- mice, a pattern that correlates with the profiles of TNFR expression in the TNFR2 +/+ controls. Thus, it seems that TNFR2-mediated editing of influenza-specific CD8 + T cells functions to limit the numbers of effectors that have localized to the site of pathology in the lung but does not modify the size of the less activated responder T cell populations in the spleen. Therefore, the massive difference in magnitude for the secondary, although not the primary, response to these D b NP 366 and D b PA 224 epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing.
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/S1074-7613(03)00351-0
Abstract: T cells play a central role in the recognition and elimination of foreign pathogens. Signals through the T cell receptor (TCR) control the extent and duration of the T cell response. To ensure that T cells are not inappropriately activated, signaling pathways downstream of the TCR are subject to multiple levels of positive and negative regulation. Herein, we describe two related proteins, Sts-1 and Sts-2, that negatively regulate TCR signaling. T cells from mice lacking Sts-1 and Sts-2 are hyperresponsive to TCR stimulation. The phenotype is accompanied by increased Zap-70 phosphorylation and activation, including its ubiquitinylated forms. Additionally, hyperactivation of signaling proteins downstream of the TCR, a marked increase in cytokine production by Sts1/2(-/-) T cells, and increased susceptibility to autoimmunity in a mouse model of multiple sclerosis is observed. Therefore, Sts-1 and Sts-2 are critical regulators of the signaling pathways that regulate T cell activation.
Publisher: Elsevier BV
Date: 10-1971
Publisher: Springer Science and Business Media LLC
Date: 08-1985
DOI: 10.1038/316484A0
Abstract: This experiment was conducted to assess the effects of packaging materials and storage environments on shelf life of papaya fruit (Carica papaya L.). A factorial combination of five packaging materials and two storage environments using randomized complete block design with three replications were used. The papaya fruits were evaluated for weight loss, percentage marketability, firmness, total soluble solids, pH, titratable acidity, ascorbic acid, reducing sugar and total sugar content. The packaged and cooled fruits remained firmer than unpackaged and evaporatively cooled fruits. Higher chemical compositions were recorded in the control fruits stored under ambient conditions during the earlier times of storage. Packaging and cooling maintained the chemical quality of papaya fruits better than the control s le fruits towards the end of storage periods. The evaporatively cooled storage combined with packaging improved the shelf life of papaya fruits by more than two fold. The polyethylene bag packaging combined with evaporatively cooled storage maintained the superior quality of papaya fruit for a period of 21 days. This integrated agro-technology is recommended for postharvest loss reduction biotechnology in hot regions.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2006
Publisher: Elsevier BV
Date: 08-1991
DOI: 10.1016/0008-8749(91)90398-U
Abstract: The characteristics of avian lymphocytes expressing surface CD8 (CT8) and T cell receptor (TCR) glycoproteins have been monitored by two-color flow microfluorimetry. Exposure of 1-month-old birds to a lethal influenza A virus, which is known to be lympholytic, significantly decreased the frequency of both the alpha beta TCR2+CT8+ and gamma delta TCR1+CT8- subsets in spleen. However, all categories of T cells showed evidence of greater mean cell size, indicating that they are responding. Inoculation of baby chicks with fowl pox virus induced a response more typical of specific immunity in the TCR2+CT8+ set, in that the lymphocytes increased in both frequency and mean cell size. Greater numbers of lymphoblasts were also found for the TCR2+CT8-, TCR1+CT8+, and TCR1+CT8- subsets, but the total cell counts for the minority TCR1+CT8- cells in spleen were consistently decreased. Immunosuppression with cyclophosphamide prior to infection eliminated 90% of the white blood cells from spleen, with the greatest effect being on the TCR1+ populations. The CT8+ alpha beta T cell response in chick spleen following exposure to a poxvirus is thus comparable to the situation observed for this subset of lymphocytes in mice infected with other viruses. However, although the gamma delta T cells increase in size, their frequency in spleen either does not change (CT8+) or is significantly decreased (CT8-).
Publisher: Proceedings of the National Academy of Sciences
Date: 29-08-2011
Abstract: Although the simultaneous engagement of multiple effector mechanisms is thought to characterize optimal CD8 + T-cell immunity and facilitate pathogen clearance, the differentiation pathways leading to the acquisition and maintenance of such polyfunctional activity are not well understood. Division-dependent profiles of effector molecule expression for virus-specific T cells are analyzed here by using a combination of carboxyfluorescein succinimidyl ester dilution and intracellular cytokine staining subsequent to T-cell receptor ligation. The experiments show that, although the majority of naive CD8 + T-cell precursors are preprogrammed to produce TNF-α soon after stimulation and a proportion make both TNF-α and IL-2, the progressive acquisition of IFN-γ expression depends on continued lymphocyte proliferation. Furthermore, the extensive ision characteristic of differentiation to peak effector activity is associated with the progressive dominance of IFN-γ and the concomitant loss of polyfunctional cytokine production, although this is not apparent for long-term CD8 + T-cell memory. Such proliferation-dependent variation in cytokine production appears tied to the epigenetic signatures within the ifnG and tnfA proximal promoters. Specifically, those cytokine gene loci that are rapidly expressed following antigen stimulation at different stages of T-cell differentiation can be shown (by ChIP) to have permissive epigenetic and RNA polymerase II docking signatures. Thus, the dynamic changes in cytokine profiles for naive, effector, and memory T cells are underpinned by specific epigenetic landscapes that regulate responsiveness following T-cell receptor ligation.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2003
Abstract: Influenza virus-specific CD8 + T cells generally recognize peptides derived from conserved, internal proteins that are not subject to antibody-mediated selection pressure. Prior exposure to any one influenza A virus (H1N1) can prime for a secondary CD8 + T cell response to a serologically different influenza A virus (H3N2). The protection afforded by this recall of established CD8 + T cell memory, although limited, is not negligible. Key characteristics of primary and secondary influenza-specific host responses are probed here with recombinant viruses expressing modified nucleoprotein (NP) and acid polymerase (PA) genes. Point mutations were introduced into the epitopes derived from the NP and PA such that they no longer bound the presenting H2D b MHC class I glycoprotein, and reassortant H1N1 and H3N2 viruses were made by reverse genetics. Conventional (C57BL/6J, H2 b , and Ig + / + ) and Ig - / - (μMT) mice were more susceptible to challenge with the single NP [HKx31 influenza A virus (HK)-NP] and PA (HK-PA) mutants, but unlike the Ig - / - mice, Ig + / + mice were surprisingly resistant to the HK-NP/-PA double mutant. This virus was found to promote an enhanced IgG response resulting, perhaps, from the delayed elimination of antigen-presenting cells. Antigen persistence also could explain the increase in size of the minor K b PB1 703 CD8 + T cell population in mice infected with the mutant viruses. The extent of such compensation was always partial, giving the impression that any virus-specific CD8 + T cell response operates within constrained limits. It seems that the relationship between protective humoral and cellular immunity is neither simple nor readily predicted.
Publisher: Elsevier BV
Date: 09-1975
DOI: 10.1016/0022-1759(75)90120-9
Abstract: In inbred or outbred mice lysis of virally modified cells by thymus-derived lymphocytes occurs only within a H-2 compatible system. Peritoneal macrophages provide a convenient source of syngeneic target cells. They are readily infected in vitro with LCM virus, and show high levels of specific 51Cr release when exposed to T cells from LCM immune mice.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2006
DOI: 10.1038/NRI1977
Abstract: Antigen-specific T-cell responses induced by infection, transplantation, autoimmunity or hypersensitivity are characterized by cells expressing biased profiles of T-cell receptors (TCRs) that are selected from a erse, naive repertoire. Here, we review the evidence for these TCR biases, focusing on crystallographic analysis of the structural constraints that determine the binding of a TCR to its ligand and the persistence of certain TCRs in an immune repertoire. We discuss the ways in which ersity in a selected TCR repertoire can contribute to protective immunity and the implications of this for vaccine design and immunotherapy.
Publisher: Elsevier BV
Date: 07-1993
DOI: 10.1016/0165-5728(93)90228-Q
Abstract: Lymphocytic choriomeningitis virus (LCMV) induces a chronic, wasting syndrome when injected intracerebrally into H-2b mice homozygous for a beta 2-microglobulin (beta 2-m (-/-)) gene disruption. These mice have very few CD8+ T cells and express little class I MHC glycoprotein, though minimal levels of the H-2Db molecule have been detected on in vitro cultured beta 2-m (-/-) cells. The underlying immunopathological process in these beta 2-m (-/-) mice is mediated by virus immune CD4+ effectors. However, adoptively transferred CD8+ T cells from normal, LCMV-infected H-2Db compatible donors induce significant (but low level) meningitis in beta 2-m (-/-) recipients. Such mice develop neither the neurological disease characteristic of LCM nor the persistent, though generally non-fatal, debility that occurs when only the CD4+ T cell subset is involved.
Publisher: The American Association of Immunologists
Date: 12-2011
Abstract: High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation and expansion. Intriguing questions remain concerning the constraints determining optimal TCR MHCI binding. The present analysis uses the TCR transgenic OT-I model to assess how varying profiles of TCR MHCI avidity influence naive CTL proliferation and the acquisition of effector function following exposure to the cognate H-2Kb/OVA257–264 (SIINFEKL) epitope and to mutants provided as peptide or in engineered influenza A viruses. Stimulating naive OT-I CD8+ T cells in vitro with SIINFEKL induced full CTL proliferation and differentiation that was largely independent of any need for costimulation. By contrast, in vitro activation with the low-affinity EIINFEKL or SIIGFEKL ligands depended on the provision of IL-2 and other costimulatory signals. Importantly, although they did generate potent endogenous responses, infection of mice with influenza A viruses expressing these same OVA257 variants failed to induce the activation of adoptively transferred naive OT-I CTLps, an effect that was only partially overcome by priming with a lipopeptide vaccine. Subsequent structural and biophysical analysis of H2-KbOVA257, H2-KbE1, and H2-KbG4 established that these variations introduce small changes at the pMHCI interface and decrease epitope stability in ways that would likely impact cell surface presentation and recognition. Overall, it seems that there is an activation threshold for naive CTLps, that minimal alterations in peptide sequence can have profound effects, and that the antigenic requirements for the in vitro and in vivo induction of CTL proliferation and effector function differ substantially.
Publisher: The American Association of Immunologists
Date: 02-2014
Abstract: The characteristics of the TCR repertoire expressed by epitope-specific CD8+ T cells can be an important determinant of the quality of immune protection against virus infection. Most studies of epitope-specific TCR repertoires focus solely on an analysis of TCR β-chains, rather than the combined TCRαβ heterodimers that confer specificity. Hence, the importance of complementary α- and β-chain pairing in determining TCR specificity and T cell function is not well understood. Our earlier study of influenza-specific TCR repertoires in a C57BL/6J mouse model described a structural basis for preferred TCRαβ pairing that determined exquisite specificity for the DbPA224 epitope from influenza A virus. We have now extended this analysis using retrogenic mice engineered to express single TCR α- or β-chains specific for the DbNP366 or DbPA224 epitopes derived from influenza A virus. We found that particular TCRαβ combinations were selected for recognition of these epitopes following infection, indicating that pairing of certain α- and β-chain sequences is key for determining TCR specificity. Furthermore, we demonstrated that some TCRαβ heterodimers were preferentially expanded from the naive repertoire in response to virus infection, suggesting that appropriate αβ pairing confers optimal T cell responsiveness to Ag.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.VACCINE.2008.07.102
Abstract: We report here on the use of a Sindbis virus-based DNA-launch RNA replicon vector (pSIN-HA) that expresses influenza hemagglutinin (HA) as an immunogen. Immunization of mice with pSIN-HA generated anti-HA antibody and CTL responses and resulted in lower lung viral titers after influenza challenge when compared to controls. Importantly, immunization with a low dose of pSIN-HA mediated significantly reduced lung viral titers following challenge at 43 weeks after the final immunization. In contrast, immunization with a non-replicon DNA vector expressing HA failed to mediate reduced lung viral titer at the same dose. This demonstrated the dose-sparing capacity of the SIN vector system and its ability to stimulate long-term memory responses, properties that are highly desirable in any vaccine formulation.
Publisher: Elsevier BV
Date: 10-1971
DOI: 10.1016/0021-9975(71)90081-8
Abstract: In March 2010, the RAND Corporation surveyed a nationally representative s le of noninstitutionalized adults age 18 and over (n=4,040) to collect data on the receipt of seasonal influenza vaccine in the United States. This overview of the survey results will inform public health officials and other stakeholders about seasonal influenza vaccination of adults shortly following the end of the vaccination season. The information on flu vaccine uptake among population groups should be of interest to those working to increase uptake among different segments of the population, including those specifically recommended for the vaccine by the Advisory Committee on Immunization Practices (ACIP) to the Centers for Disease Control and Prevention. Survey findings indicate that during the 2009-2010 vaccination season, 39 percent of all U.S. adults were vaccinated against seasonal influenza, 45 percent of adults specifically recommended for vaccination were vaccinated, and 48 percent of vaccinated adults received the vaccine at a doctor's office or medical clinic.
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/0008-8749(92)90015-H
Abstract: The prevalence of gamma delta T cells in bronchoalveolar lavage (BAL) populations recovered from the respiratory tract of young, adult C57BL/6J mice infected intranasally (i.n.) with Sendai virus has been assessed by FACS-phenotyping, and by probing cytocentrifuge preparations for expression of TCR gamma mRNA. The surface gamma delta TCR+ set comprised from 5 to 20% of the inflammatory lymphocytes in sequential s les taken throughout the course of this nonfatal viral pneumonia. The BAL population also contained numerous cells expressing mRNA for C gamma 1/2 and C gamma 4 the C-regions were utilized for productive TCR gene rearrangement. Sorting the lymphocytes from the BAL established that greater than 90% of both the TCR gamma and TCR beta mRNA partitioned to cells with the appropriate surface TCR phenotype, while less than 7% of the TCR mRNA+ cells in the total inflammatory exudate were phagocytes that engulfed latex particles. Both the frequency and the total numbers of the gamma delta TCR+ and TCR gamma mRNA+ cells were increased in mice depleted of alpha beta T cells by in vivo treatment with mAbs to CD4 and CD8, indicating that the CD4+ and CD8+ alpha beta and CD4-8- gamma delta T cell subsets may operate independently in this virus disease. The C gamma 1/2 mRNA phenotype predominated throughout the course of the active infection, with a transition to maximal prevalence of the C gamma 4 mRNA+ set occurring very late (Day 20) in the resolving inflammatory process. Large numbers of macrophages expressing mRNA (greater than 50%) for a mammalian 65-kDa heat shock protein (hsp65), a possible target for some of the gamma delta T cells, were present early (Days 5-7) and remained at lower levels (less than 20%) thereafter. These hsp65 mRNA+ macrophages were much less apparent in BAL populations from mice depleted concurrently of the CD4+ and CD8+ T cell subsets, indicating that exposure to Sendai virus alone is not the major factor inducing the transcription of this endogenous gene. These experiments thus establish that gamma delta T cells are a minority of the infiltrating lymphocytes in Sendai virus pneumonia and provide new insights into the spectrum of hsp65 mRNA and TCR gamma mRNA expression during an inflammatory process.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-04-2005
Abstract: The restriction of influenza A virus replication to mouse respiratory epithelium means that this host response is anatomically compartmentalized, on the one hand, to sites of T cell stimulation and proliferation in the secondary lymphoid tissue and, on the other hand, to the site of effector T cell function and pathology in the pneumonic lung. Thus, it is hardly surprising that virus-specific CD8 + T cells recovered by bronchoalveolar lavage (BAL) from the infected respiratory tract seem more “activated” in terms of both cytolytic activity and cytokine production than those cells isolated from the spleen. The present analysis uses Affymetrix microarray technology to compare profiles of gene expression in these two lineage-related, yet anatomically separate, lymphocyte populations. Ninety differentially expressed genes were identified for influenza-specific CD8 + D b NP 366 + T cells obtained directly ex vivo by BAL or spleen disruption, with nine genes being further analyzed by quantitative, real-time PCR at the population level. Integrin αE, for ex le, was shown by Affymetrix and real-time mRNA analyses and then by single-cell PCR and protein staining to be present at a much higher prevalence on the BAL CD8 + D b NP 366 + set. The unpredicted finding, however, was that mRNA expression for 75% of the 90 genes was lower in T cells from the BAL than from the spleen. Apparently, the localization of virus-specific CD8 + T cells to the site of virus-induced pathology is associated with a narrowing, or “focusing,” of gene expression that favors enhanced effector function in the damaged, “high-antigen load” environment of the pneumonic lung.
Publisher: Wiley
Date: 26-08-2010
Abstract: TCR repertoire ersity can influence the efficacy of CD8(+) T-cell populations, with greater breadth eliciting better protection. We analyzed TCR beta ersity and functional capacity for influenza-specific CD8(+) T cells expressing a single TCR alpha chain. Mice (A7) transgenic for the H2K(b)OVA(257-264)-specific V alpha 2.7 TCR were challenged with influenza to determine how fixing this "irrelevant" TCR alpha affects the "public" and restricted D(b)NP(366) (+)CD8(+) versus the "private" and erse D(b)PA(224) (+)CD8(+) responses. Though both D(b)NP(366) (+)CD8(+) and D(b)PA(224) (+)CD8(+) sets are generated in virus-primed A7 mice, the constrained D(b)NP(366) (+)CD8(+) population lacked the characteristic, public TCRV beta 8.3, and consequently was reduced in magnitude and pMHC-I avidity. For the more erse D(b)PA(224) (+)CD8(+) T cells, this particular forcing led to a narrowing and higher TCR beta conservation of the dominant V beta 7, though the responses were of comparable magnitude to C57BL/6J controls. Interestingly, although both the TCR beta ersity and the cytokine profiles were reduced for the D(b)NP(366) (+)CD8(+) and D(b)PA(224) (+)CD8(+) sets in spleen, the latter measure of polyfunctionality was comparable for T cells recovered from the infected lungs of A7 and control mice. Even "sub-optimal" TCR alpha beta pairs can operate effectively when exposed in a milieu of high virus load. Thus, TCR beta ersity is important for optimal TCR alpha beta pairing and function when TCR alpha is limiting.
Publisher: Microbiology Society
Date: 02-2014
Abstract: Type I alveolar epithelial cells are a replicative niche for influenza in vivo , yet their response to infection is not fully understood. To better characterize their cellular responses, we have created an immortalized murine lung epithelial type I cell line (LET1). These cells support spreading influenza virus infection in the absence of exogenous protease and thus permit simultaneous analysis of viral replication dynamics and host cell responses. LET1 cells can be productively infected with human, swine and mouse-adapted strains of influenza virus and exhibit expression of an antiviral transcriptional programme and robust cytokine secretion. We characterized influenza virus replication dynamics and host responses of lung type I epithelial cells and identified the capacity of epithelial cell-derived type I IFN to regulate specific modules of antiviral effectors to establish an effective antiviral state. Together, our results indicate that the type I epithelial cell can play a major role in restricting influenza virus infection without contribution from the haematopoietic compartment.
Publisher: Annual Reviews
Date: 04-2007
DOI: 10.1146/ANNUREV.IMMUNOL.25.022106.141644
Abstract: My research career has focused on complex experimental systems, principally virus-induced infectious processes. I have always run my own experimental program and never had a major mentor, although I have had many great colleagues. After graduating from the School of Veterinary Science at the University of Queensland, Australia, I worked for nine years on diseases of domestic animals. During that interval I completed a part-time PhD at the University of Edinburgh while employed as an experimental neuropathologist. Returning to the John Curtin School of Medical Research in Canberra, I focused on cell-mediated immunity, started to work seriously with mice, and thus became both an immunologist and a basic medical scientist. It was there in 1973 that Rolf Zinkernagel and I discovered MHC I–restricted CD8 + T cell recognition, a finding that, together with the “single T cell receptor/altered self” hypothesis that we developed to explain our results, led to the 1996 Nobel Prize for Physiology or Medicine. Part of my focus since then has been to communicate the societal value and power of science to the broader community. As my scientific life is not yet over, I confine the present historical account to the twentieth century.
Publisher: Oxford University Press (OUP)
Date: 09-11-2006
Publisher: Public Library of Science (PLoS)
Date: 12-08-2010
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/JVI.00470-09
Abstract: There is an urgent need for human immunodeficiency virus (HIV) vaccines that induce robust mucosal immunity. Influenza A viruses (both H1N1 and H3N2) were engineered to express simian immunodeficiency virus (SIV) CD8 T-cell epitopes and evaluated following administration to the respiratory tracts of 11 pigtail macaques. Influenza virus was readily detected from respiratory tract secretions, although the infections were asymptomatic. Animals seroconverted to influenza virus and generated CD8 and CD4 T-cell responses to influenza virus proteins. SIV-specific CD8 T-cell responses bearing the mucosal homing marker β7 integrin were induced by vaccination of naïve animals. Further, SIV-specific CD8 T-cell responses could be boosted by recombinant influenza virus-SIV vaccination of animals with already-established SIV infection. Sequential vaccination with influenza virus-SIV recombinants of different subtypes (H1N1 followed by H3N2 or vice versa) produced only a limited boost in immunity, probably reflecting T-cell immunity to conserved internal proteins of influenza A virus. SIV challenge of macaques vaccinated with an influenza virus expressing a single SIV CD8 T cell resulted in a large anamnestic recall CD8 T-cell response, but immune escape rapidly ensued and there was no impact on chronic SIV viremia. Although our results suggest that influenza virus-HIV vaccines hold promise for the induction of mucosal immunity to HIV, broader antigen cover will be needed to limit cytotoxic T-lymphocyte escape.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.PHARMTHERA.2008.08.007
Abstract: Antigen-specific CD8+ T cells play an important role in virus clearance. Here we review the current understanding of influenza virus-specific CD8+ T cell immunity in experimental mouse models and humans. The characteristics and nature of CD8+ T cell killing are discussed, as is the selection and maintenance of the influenza-specific effector and memory repertoires. Consideration is given to vaccine strategies and to the effects of ageing. Understanding the complexities of CD8+ T cell mediated immunity and memory has the potential for improving vaccine design, particularly to combat pandemics caused by newly emerging influenza viruses.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2015
DOI: 10.1038/NRI3905
Abstract: Naive CD8(+) T cells give rise to cytotoxic T lymphocytes (CTLs), which promote the effective eradication of viruses and tumours. Although the past decades have seen enormous advances in cellular immunology, a precise understanding of the key elements that determine the specificity and magnitude of primary CTL responses has been lacking. However, recent technological advances have allowed us to more accurately identify, characterize and quantitate key determinants that define the specificity and magnitude of CD8(+) T cell-mediated immunity. This Review discusses the technical and conceptual advances that have markedly changed our understanding of the determinants of primary CTL responses.
Publisher: Elsevier BV
Date: 04-1971
DOI: 10.1016/0021-9975(71)90103-4
Abstract: Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional in idual monoubiquitin modifications onto CRL client substrates. Our data define ARIH1 as a component of the human CRL system, demonstrate that ARIH1 can efficiently and specifically mediate monoubiquitylation of several CRL substrates, and establish principles for how two distinctive E3s can reciprocally control each other for simultaneous and joint regulation of substrate ubiquitylation. These studies have broad implications for CRL-dependent proteostasis and mechanisms of E3-mediated UB ligation.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-01-2006
Abstract: Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8 + T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP 366–374 ) and acid polymerase (PA 224–233 ) peptides presented by H2D b have been analyzed by disabling (N5→ Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of D b NP 366 [epitope consisting of viral nucleoprotein (NP) amino acid residues 366–374 complexed with the H2D b MHC class I glycoprotein] and D b PA 224 (H2D b +PA 224–233 ) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the D b NP 366 - and D b PA 224 -specific T cell subsets generated after infection of mice. Comparison of D b NP 366 - and D b PA 224 -specific CD8 + T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8 + T cell precursor frequency. Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers.
Publisher: Elsevier BV
Date: 1988
DOI: 10.1016/0165-5728(88)90020-3
Abstract: Induction of experimental allergic encephalomyelitis (EAE) in Lewis rats by injection of guinea pig (GP) spinal cord homogenate (SCH) plus adjuvant (SCH-CFA) can be inhibited by treatment with the iron chelating agent desferrioxamine (DFOM). Interestingly, induction of EAE with purified myelin basic protein (BP-CFA) is not inhibited with DFOM. This dichotomy does not appear to be due to any quantitative differences in the two inocula since minimal clinical EAE produced by threshold levels of BP is not inhibited with DFOM. Passive EAE is not inhibited irrespective of the type of encephalitogen used to sensitize the donors. This suggests that the inhibitory effect of DFOM is acting on the afferent limb of the immune response to SCH-CFA. Injection of BP-CFA and SCH-CFA into the same site, mixing BP with central nervous system (CNS) lipids, or incorporating BP into liposomes, all induce EAE which can be partially inhibited by treatment with DFOM. These results support the hypothesis that the close association of lipids with the encephalitogen (i.e. BP) in SCH required extensive lipid breakdown before adequate antigen presentation can occur, and it is at this level that DFOM exerts its inhibitory effect.
Publisher: Microbiology Society
Date: 04-2005
Abstract: The severity of disease caused in humans by H5N1 influenza viruses remains unexplained. The NS gene of Hong Kong H5N1/97 viruses was shown to contribute to high pathogenicity of reassortants in a pig model. However, the molecular pathogenesis and host immune response underlying this phenomenon remain unclear. Here, in a mouse model, H1N1 A/Puerto Rico/8/34 (PR/8) reassortants that contained the H5N1/97 NS gene, the H5N1/01 NS gene, or an altered H5N1/97 NS gene encoding a Glu 92 →Asp substitution in NS1 was studied. The pathogenicity of reassortant viruses, the induction of cytokines and chemokine CXCL1 (KC) in the lungs and specific B- and T-cell responses was characterized. In mice infected with reassortant virus containing the H5N1/97 NS gene, the mouse lethal dose (50 %) and lung virus titres were similar to those of PR/8, which is highly pathogenic to mice. This reassortant virus required two more days than PR/8 to be cleared from the lungs of infected mice. Reassortants containing the altered H5N1/97 NS gene or the H5N1/01 NS gene demonstrated attenuated pathogenicity and lower lung titres in mice. Specific B- and T-cell responses were consistent with viral pathogenicity and did not explain the delayed clearance of the H5N1/97 NS reassortant. The reassortant induced elevated pulmonary concentrations of the inflammatory cytokines IL1 α , IL1 β , IL6, IFN- γ and chemokine KC, and decreased concentrations of the anti-inflammatory cytokine IL10. This cytokine imbalance is reminiscent of the clinical findings in two humans who died of H5N1/97 infection and may explain the unusual severity of the disease.
Publisher: American Society for Microbiology
Date: 15-01-2010
DOI: 10.1128/JVI.01535-09
Abstract: Human infections with highly pathogenic H5N1 avian influenza A viruses in the last decade have legitimized fears of a long-predicted pandemic. We thus investigated the response to secondary infections with an engineered, but still highly virulent, H5N1 influenza A virus in the C57BL/6 mouse model. Mice primed with the H1N1 A/Puerto Rico/8/34 (PR8) virus were partially protected from lethality following respiratory infection with the modified H5N1 virus A/Vietnam/1203/04 (ΔVn1203). In contrast, those that had been comparably exposed to the HKx31 (H3N2) virus succumbed to the ΔVn1203 challenge, despite similarities in viral replication, weight loss, and secondary CD8 + -T-cell response characteristics. All three viruses share the internal genes of PR8 that are known to stimulate protective CD8 + -T-cell-mediated immunity. This differential survival of PR8- and HKx31-primed mice was also apparent for antibody-deficient mice challenged with the ΔVn1203 virus. The relative protection afforded by PR8 priming was abrogated in tumor necrosis factor-deficient (TNF −/− ) mice, although lung fluids from the B6 HKx31-primed mice contained more TNF early after challenge. These data demonstrate that the nature of the primary infection can influence pathological outcomes following virulent influenza virus challenge, although the effect is not clearly correlated with classical measures of CD8 + -T-cell-mediated immunity.
Publisher: Springer Science and Business Media LLC
Date: 23-06-1994
DOI: 10.1038/369652A0
Abstract: Although some viruses, particularly the herpes viruses, may never be eliminated from the body, others like influenza A, regularly reinfect humans and boost waning crossreactive CD8+ T-cell immunity. Prolonged T-cell memory is found for viruses that are unlikely to be re-encountered and which do not persist in the host genome, indicating that CD8+ T-cell memory might be independent of continued (or sporadic) antigenic exposure. A feature of virus-specific CD8+ T-cell memory is that antigen-specific cytotoxic T-lymphocyte precursors (CTLp) are greatly increased and remain high throughout life. The idea that persistence of the inducing antigen is essential is based on experiments in which adoptively transferred CD8+ memory T cells could not be detected for more than a few weeks in naive recipient mice without secondary challenge. Here we show that restimulation of such chimaeric mice with an inducing Sendai virus antigen increases the clonal burst size more than 7-fold within 8 days, making memory CTLp easier to detect in the longer term. We find that Sendai-virus-specific CTLp are maintained for > 250 days in irradiated uninfected recipients, including reconstituted beta 2-microglobulin-/- mice. To determine whether a source of viral peptide can persist after primary infection, we gave Sendai-virus-specific Thy1.1+ memory spleen cells to naive mice that had been minimally depleted of Thy1.2+ T cells, or to comparable recipients that had recovered from infection with Sendai virus or influenza virus. Although antibody against Sendai virus was never found in the naive recipients, Sendai-virus-specific CD8+ memory T cells were maintained equally well in each case for > 100 days after cell transfer. We find no evidence for persisting depots of viral protein that might feed into the endogenous processing pathway and maintain virus-specific CD8+ T-cell memory.
Publisher: Elsevier BV
Date: 19-11-1993
Publisher: Elsevier BV
Date: 07-2008
Publisher: Elsevier BV
Date: 07-1972
DOI: 10.1016/0021-9975(72)90015-1
Abstract: Acute Helicobacter pylori infection of gastric epithelial cells induces CagA oncoprotein- and peptidoglycan (SLT)-dependent mobilization of NF-κB p50 homodimers that bind to H-K-ATPase α-subunit (HKα) promoter and repress HKα gene transcription. This process may facilitate gastric H. pylori colonization by induction of transient hypochlorhydria. We hypothesized that H. pylori also regulates HKα expression posttranscriptionally by miRNA interaction with HKα mRNA. In silico analysis of the HKα 3' untranslated region (UTR) identified miR-1289 as a highly conserved putative HKα-regulatory miRNA. H. pylori infection of AGS cells transfected with HKα 3' UTR-Luc reporter construct repressed luciferase activity by 70%, whereas ΔcagA or Δslt H. pylori infections partially abrogated repression. Transfection of AGS cells expressing HKα 3' UTR-Luc construct with an oligoribonucleotide mimetic of miR-1289 induced maximal repression (54%) of UTR activity within 30 min UTR activity was unchanged by nontargeting siRNA transfection. Gastric biopsies from patients infected with cagA(+) H. pylori showed a significant increase in miR-1289 expression compared with uninfected patients or those infected with cagA(-) H. pylori. Finally, miR-1289 expression was necessary and sufficient to attenuate biopsy HKα protein expression in the absence of infection. Taken together, these data indicate that miR-1289 is upregulated by H. pylori in a CagA- and SLT-dependent manner and targets HKα 3' UTR, affecting HKα mRNA translation. The sensitivity of HKα mRNA 3' UTR to binding of miR-1289 identifies a novel regulatory mechanism of gastric acid secretion and offers new insights into mechanisms underlying transient H. pylori-induced hypochlorhydria.
Publisher: The Royal Society
Date: 11-08-2005
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-04-1998
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: Future Medicine Ltd
Date: 03-2010
DOI: 10.2217/FVL.10.3
Abstract: Seasonal influenza virus infection is a leading cause of illness and mortality in young children and the elderly each year. Current influenza vaccines generate protective antibody responses however, these must be given annually to provide protection against serologically distinct viruses. By contrast, CD8 + T cells are capable of recognizing conserved antigenic determinants within the influenza virion and, as such, may provide protection against a number of variant strains of the virus. CD8 + T cells play a critical key role in controlling and resolving influenza virus infections via the production of cytokines and cytolytic mediators. This article focuses on the induction of the influenza-specific CD8 + T-cell response and how these cells acquire and maintain effector function after induction. Moreover, we discuss how cytotoxic T-lymphocyte function correlates with protection following vaccination.
Publisher: Springer Science and Business Media LLC
Date: 11-1998
DOI: 10.1038/3233
Abstract: Inherited deficiency of the CD40 ligand (X-linked hyper-IgM syndrome) is characterized by failure of immunoglobulin isotype switching and severe defects of cell-mediated immunity. To test the potential for gene transfer therapy to correct this disorder, we transduced murine bone marrow or thymic cells with a retroviral vector containing the cDNA for the murine CD40 ligand (CD40L) and injected them into CD40L-/- mice. Even low-level, constitutive expression of the transgene stimulated humoral and cellular immune functions in these mice. With extended follow-up, however, 12 of 19 treated mice developed T-lymphoproliferative disorders, ranging from polyclonal increases of lymphoblasts to overt monoclonal T-lymphoblastic lymphomas that involved multiple organs. Our findings show that constitutive (rather than tightly regulated), low-level expression of CD40L can produce abnormal proliferative responses in developing T lymphocytes, apparently through aberrant interaction between CD40L+ and TCRalphabeta+CD40+ thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-03-2010
Abstract: Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered to function as a series of “independent pegs” that either anchor the peptide (p) to the MHC-I and/or interact with the spectrum of αβ-T-cell receptors (TCRs) specific for the pMHC-I epitope in question. Mining of the extensive pMHC-I structural database established that many self- and viral peptides show extensive and direct interresidue interactions, an unexpected finding that has led us to the idea of “constrained” peptides. Mutational analysis of two constrained peptides (the HLA B44 restricted self-peptide (B44DPα–EEFGRAFSF) and an H2-D b restricted influenza peptide (D b PA, SSLENFRAYV) demonstrated that the conformation of the prominently exposed arginine in both peptides was governed by interactions with MHC-I-orientated flanking residues from the peptide itself. Using reverse genetics in a murine influenza model, we revealed that mutation of an MHC-I-orientated residue (SSLEN F RAYV → SSLEN A RAYV) within the constrained PA peptide resulted in a diminished cytotoxic T lymphocyte (CTL) response and the recruitment of a limited pMHC-I specific TCR repertoire. Interactions between in idual peptide positions can thus impose fine control on the conformation of pMHC-I epitopes, whereas the perturbation of such constraints can lead to a previously unappreciated mechanism of viral escape.
Publisher: The American Association of Immunologists
Date: 12-2010
Abstract: Cytokine polyfunctionality has recently emerged as a correlate of effective CTL immunity to viruses and tumors. Although the determinants of polyfunctionality remain unclear, there are published instances of a link between the production of multiple effector molecules and the peptide plus MHC class I molecule avidity of T cell populations. Influenza A virus infection of C57BL/6J mice induces CTL populations specific for multiple viral epitopes, each with varying proportions of monofunctional (IFN-γ+ only) or polyfunctional (IFN-γ+TNF-α+IL-2+) CTLs. In this study, we probe the link between TCR avidity and polyfunctionality for two dominant influenza epitopes (DbNP366 and DbPA224) by sequencing the TCR CDR3β regions of influenza-specific IFN-γ+ versus IFN-γ+IL-2+ cells, or total tetramer+ versus high-avidity CTLs (as defined by the peptide plus MHC class I molecule-TCR dissociation rate). Preferential selection for particular clonotypes was evident for the high-avidity DbPA224-specific set but not for any of the other subsets examined. These data suggest that factors other than TCRβ sequence influence cytokine profiles and demonstrate no link between differential avidity and polyfunctionality.
Publisher: The American Association of Immunologists
Date: 06-2011
Abstract: Earlier studies of influenza-specific CD8+ T cell immunodominance hierarchies indicated that expression of the H2Kk MHC class I allele greatly diminishes responses to the H2Db-restriced DbPA224 epitope (acid polymerase, residues 224–233 complexed with H2Db). The results suggested that the presence of H2Kk during thymic differentiation led to the deletion of a prominent Vβ7+ subset of DbPA224-specific TCRs. The more recent definition of DbPA224-specific TCR CDR3β repertoires in H2b mice provides a new baseline for looking again at this possible H2Kk effect on DbPA224-specific TCR selection. We found that immune responses to several H2Db- and H2Kb-restricted influenza epitopes were indeed diminished in H2bxk F1 versus homozygous mice. In the case of DbPA224, lower numbers of naive precursors were part of the explanation, though a similar decrease in those specific for the DbNP366 epitope did not affect response magnitude. Changes in precursor frequency were not associated with any major loss of TCR ersity and could not fully account for the diminished DbPA224-specific response. Further functional and phenotypic characterization of influenza-specific CD8+ T cells suggested that the expansion and differentiation of the DbPA224-specific set is impaired in the H2bxk F1 environment. Thus, the DbPA224 response in H2bxk F1 mice is modulated by factors that affect the generation of naive epitope-specific precursors and the expansion and differentiation of these T cells during infection, rather than clonal deletion of a prominent Vβ7+ subset. Such findings illustrate the difficulties of predicting and defining the effects of MHC class I ersification on epitope-specific responses.
Publisher: Elsevier BV
Date: 05-2011
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-01-2012
Publisher: American Society for Microbiology
Date: 15-08-2001
DOI: 10.1128/JVI.75.16.7744-7748.2001
Abstract: Major histocompatibility complex class II-mediated antigen presentation after intranasal infection with murine gammaherpesvirus 68 differs in mediastinal lymph nodes and spleen. Evidence that virus-specific CD4 + T cells were being stimulated was found as late as 6 to 8 months after infection, and cells specific for the viral gp150 67–83 and ORF11 168–180 peptides were maintained as a fairly stable proportion of the total response.
Publisher: Elsevier BV
Date: 09-1989
DOI: 10.1016/0165-5728(89)90098-2
Abstract: The role of the non-major histocompatibility complex (MHC) genetic background in the development of lymphocytic choriomeningitis (LCM) was examined for a range of mouse strains of the H-2k haplotype. The onset of meningitis relative to the time of injection of LCM virus was delayed and the maximal level of cellular extravasation into cerebrospinal fluid was lower in C3H/HeJ and CBA/H compared with AKR/J, B10.Br and BALB/c.H-2k mice. Adoptive transfer experiments indicated that the C3H mice are genuine low responders, but immune spleen cells from the CBA/H were as potent on a cell-for-cell basis as those from the AKR/J. Further analysis with CBA/H, AKR/J and (CBA/H x AKR/J)F1 mice showed that the pattern of high response for the AKR/J was dominant, with the differential kinetics of the development of meningitis correlating with the cellularity of the cervical lymph nodes. Thus, the generation of the LCM inflammatory process is not dictated solely by the MHC phenotype.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-02-2004
Abstract: Can CD4 + and CD8 + “memory” T cells that are generated and maintained in the context of low-level virus persistence protect, in the absence of antibody, against a repeat challenge with the same pathogen? Although immune T cells exert effective, long-term control of a persistent γ-herpesvirus (γHV68) in Ig –/– μMT mice, subsequent exposure to a high dose of the same virus leads to further low-level replication in the lung. This lytic phase in the respiratory tract is dealt with effectively by the recall of memory T cells induced by a γHV68 recombinant (M3LacZ) that does not express the viral M3 chemokine binding protein. At least for the CD8 + response, greater numbers of memory T cells confer enhanced protection in the M3LacZ-immune mice. However, neither WT γHV68 nor the minimally persistent M3LacZ primes the T cell response to the extent that a WT γHV68 challenge fails to establish latency in the μMT mice. Memory CD4 + and CD8 + T cells thus act together to limit γHV68 infection but are unable to provide absolute protection against a high-dose, homologous challenge.
Publisher: Springer Science and Business Media LLC
Date: 24-03-2013
DOI: 10.1038/NI.2563
Publisher: Springer Science and Business Media LLC
Date: 09-01-2009
DOI: 10.1038/CDD.2008.176
Abstract: Time-lapse video microscopy allows analysis of the interaction between in idual CTLs and adherent peptide-pulsed targets, from contact, to lymphocyte detachment, APC rounding, phosphatidylserine exposure and finally loss of plasma membrane integrity characteristic of end-stage apoptosis. Using in vitro-stimulated effectors specific for the ovalbumin K(b)OVA(257) (OT-I) and influenza A virus D(b)NP(366) and D(b)PA(224) epitopes, no significant correlation was found between the duration of CTL contact and the time to phosphatidylserine exposure or loss of membrane integrity. Furthermore, there were minimal indications that transgenic T cells specific for the K(b)OVA(257) epitope (TCR) ersity had any effect. However, when the analysis was repeated with D(b)NP(366) and D(b)PA(224)-specific CTLs recovered directly from the lungs of mice with influenza pneumonia, the lower avidity D(b)NP(366)-specific set was found to elute much more quickly. Shorter contact time may allow in idual CTLs to lyse more targets, suggesting that lower TCR/epitope avidity may be more beneficial than higher epitope avidity for cell-mediated immunity.
Publisher: Proceedings of the National Academy of Sciences
Date: 12-02-2008
Abstract: TCR repertoire ersity has been convincingly shown to facilitate responsiveness of CD8 + T cell populations to mutant virus peptides, thereby safeguarding against viral escape. However, the impact of repertoire ersity on the functionality of the CD8 + T cell response to cognate peptide-MHC class I complex (pMHC) recognition remains unclear. Here, we have compared TCRβ chain repertoires of three influenza A epitope-specific CD8 + T cell responses in C57BL/6 (B6) mice: D b NP 366–374 , D b PA 224–233 , and a recently described epitope derived from the +1 reading frame of the influenza viral polymerase B subunit (residues 62–70) (D b PB1-F2 62 ). Corresponding to the relative antigenicity of the respective pMHCs, and irrespective of the location of prominent residues, the D b PA 224 - and D b PB1-F2 62 -specific repertoires were similarly erse, whereas the D b NP 366 population was substantially narrower. Importantly, parallel analysis of response magnitude, cytotoxicity, TCR avidity, and cytokine production for the three epitope-specific responses revealed no obvious functional advantage conferred by increased T cell repertoire ersity. Thus, whereas a erse repertoire may be important for recognition of epitope variants, its effect on the response to cognate pMHC recognition appears minimal.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.VACCINE.2004.10.030
Abstract: Despite decades of work, an effective HIV vaccine remains elusive. In an effort to elicit protective immunity, investigators have sought to define vaccines able to elicit durable HIV-specific B-cell and T-cell activities. Additionally, vaccines are sought which can induce antibodies of a variety of isotypes, as each isotype possesses unique attributes in terms of opsonization, Fc receptor binding capacity, complement fixation and location. One prominent new vaccine strategy, applied to numerous distinct antigenic systems is the prime boost-regimen, with DNA, vaccinia virus (VV), and/or purified recombinant protein. To examine the durability, location and isotype distribution of responses induced by prime-boost regimens, we tested successive immunizations with DNA, VV and protein (D-V-P), comparing three forms of protein inoculations: (i) purified protein administered intramuscularly with complete Freunds adjuvant, (ii) purified protein administered intranasally, and (iii) purified protein conjugated to oxidized mannan, administered intranasally. We found that all three protocols elicited serum antibodies of multiple isotypes, with serum IgA being most prominent among mice immunized with mannan-conjugated protein. All D-V-P protocols, regardless of protein form or route, also elicited antibody responses at mucosal surfaces. In bronchoalveolar lavage, a tendency toward IgA production was again most prominent in mice boosted with the protein-mannan conjugate. Both B-cell and T-cell responses were sustained for more than 1 year post-immunization following each form of vaccination. Contemporaneous with long-lasting serum and mucosal antibodies were antibody forming cells in the bone marrow of primed animals. Results highlight the D-V-P vaccination strategy as a promising approach for attaining durable, multi-isotype B-cell and T-cell activities toward HIV.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-03-2013
Abstract: A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8 + T cells responding to the immunodominant D b NP 366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D b NP 366 -specific CD8 + T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial “hole” in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor ersity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8 + T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.JIM.2007.01.019
Abstract: Analysis of T cell receptor (TCR) data has become a crucial element in many studies aimed at better understanding the evolution of the T cell repertoire and the role of TCR ersity in immune responses. In this paper we focus on comparing the ersity between s les of the TCR repertoire. We discuss some of the limitations and potential problems inherent in some of the more popular approaches to comparing s les of the TCR repertoire and we suggest alternate methods that both avoid these problems and enrich the analysis of TCR data. Ex les from published studies of the CD8(+) T cell responses to the influenza A virus D(b)NP(366) and D(b)PA(224) epitopes in mice are used to demonstrate the implementation of these methods. One ex le involves a comparison between the central and effector memory T cell subsets, defined on the basis of CD62L expression, and the other examines changes in the TCR repertoire over time.
Publisher: Elsevier BV
Date: 1993
Abstract: The effects of depleting CD4+ and CD8+ T cells on macrophage recruitment have been analyzed for bronchoalveolar lavage (BAL) populations from mice with primary or secondary influenza pneumonia. Macrophages were characterized by both the capacity to engulf latex particles and the expression of mRNA for a 65 kD heat shock protein (hsp65). The localization of hsp65 mRNA+ cells to the pneumonic lung was greatly enhanced in the secondary response. Eliminating the CD4+ and CD8+ T cells decreased the prevalence of hsp65 mRNA+latex+ macrophages as much as seven-fold, though the frequency of latex+ cells was higher in the residual inflammatory process. The CD4-8- gamma delta T cells were also relatively enriched in the BAL from the depleted mice. However, the localization of gamma delta T cells to the pneumonic lung does not compensate either quantitatively or qualitatively for the lack of the CD4+ and CD8+ alpha beta T-cell subsets, which are responsible for activating a substantial proportion of the phagocytic cells to express transcripts of an endogenous hsp65 gene.
Publisher: Elsevier BV
Date: 08-2003
Publisher: AMPCo
Date: 11-08-2014
DOI: 10.5694/MJA14.01074
Publisher: Proceedings of the National Academy of Sciences
Date: 13-06-2006
Abstract: Single-cell analysis of endogenous, primary CD8 + T cell responses to the influenza D b NP 366 and D b PA 224 epitopes indicates that prominent clonotypes bearing “public” or “shared” T cell receptors (TCRs) subset early into CD62L hi and CD62L lo populations. The CD62L lo effectors ide more and are rapidly eliminated during the contraction phase, whereas stable CD62L hi memory populations persist in the long-term. Reflecting the high frequency of small CD62L hi clones expressing “private” TCRs, the TCR ersity range per mouse is generally two times higher within the CD62L hi CD8 + D b NP 366 + set (1.6 times higher for CD62L hi CD8 + D b PA 224 + ) from 8 to days after antigen challenge. Memory CD8 + CD62L hi T cell precursors thus segregate from the outset into populations expressing “best-fit” and “suboptimal” TCR characteristics, with this pattern being maintained stably thereafter. Hence, our analysis suggests that early establishment of influenza-specific memory within the CD8 + CD62L hi subset preserves clonal ersity and prevents “overdominance” by a few public, or shared, clones.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-04-1999
Abstract: The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic γ-herpesvirus. Both CD4 + and CD8 + T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers in the lung. However, the further neutralization of IFN-γ diminishes the effectiveness of the CD4 + T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4 + effectors operate optimally when there is the potential for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-γ produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent depletion of both the CD4 + population and IFN-γ. These experiments raise the possibility that the defective control of intercurrent γ-herpesvirus infections in patients with AIDS not only is due solely to the absence of helper T cells but also reflects the loss of an important set of CD4 + effectors.
Publisher: Springer Science and Business Media LLC
Date: 03-1991
DOI: 10.1007/BF01225275
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-2013
Publisher: Elsevier BV
Date: 06-2004
Publisher: Wiley
Date: 29-04-2014
DOI: 10.1038/ICB.2014.28
Abstract: CD40-CD154 (CD40 ligand) interactions are essential for the efficient priming of CD8(+) cytotoxic T lymphocyte (CTL) responses. This is typically via CD4(+)CD154(+) T-cell-dependent 'licensing' of CD40(+) dendritic cells (DCs) however, DCs infected with influenza A virus (IAV) upregulate CD154 expression, thus enabling efficient CTL priming in the absence of CD4(+) T activation. Therefore, it is unclear whether CD4 T cells and DCs have redundant or unique roles in the priming of primary and secondary CTL responses after infection. Here we determine the precise cellular interactions involved in CD40-CD154 regulation of both primary and secondary IAV-specific CTL responses. Infection of both CD40 KO and CD154 KO mice resulted in diminished quantitative and qualitative CTL responses after both primary and secondary infection. Adoptive transfer of CD154(+), but not CD154 KO, CD4 T cells into CD154 KO mice restored both primary and secondary IAV-specific CD8 T-cell responses. These data show that, although CD154 expression on CD4 T cells and other cell types (that is, DCs) may be redundant for the priming of primary CTL responses, CD154 expression by CD4 T cells is required for the priming memory CD8 T cells that are capable of fully responding to secondary infection.
Publisher: The American Association of Immunologists
Date: 13-01-2010
Publisher: Elsevier BV
Date: 09-1998
Abstract: Murine gammaherpesvirus-68 (MHV-68) induces high levels of interleukin (IL)-6 production in both naive and primed lymphocyte populations. Mice that are homozygous (-/-) for deletion of the IL-6 gene were used to investigate the role of this cytokine in MHV-68 infection. The results showed that IL-6 is not essential for clearance of infectious MHV-68 from the lung or for the establishment, or control, of viral latency. Both IL-6 +/+ and -/- mice eliminated replicating virus from the respiratory tract within 15 days of infection, and their lungs remained clear of infectious virus for >/=150 days. Interestingly, the IL-6 -/- mice had both increased numbers of natural killer (NK)1.1+ cells and higher levels of NK cell activity than the +/+ controls at 10-15 days after infection. However, there was no difference in the cytotoxic T cell activity between the two groups of mice. Levels of latent virus were comparable in IL-6 +/+ and -/- mice over the time course studied. Furthermore, analysis of the numbers, types, and activation status of the various leukocyte subsets (other than NK cells) in the bronchoalveolar lavage population, lymph nodes, and spleens of +/+ and -/- mice revealed no striking differences. Apart from the expected lack of IL-6, cytokine profiles were not dramatically altered in IL-6 -/- mice. Thus, there is no evidence for an obligatory role for IL-6 in T cell activation during infection with MHV-68.
Publisher: Wiley
Date: 04-1999
DOI: 10.1046/J.1440-1711.1999.00812.X
Abstract: Scientific discoveries are not made in isolation. Innovation depends on resources, both intellectual and physical. A primary requirement is the development and maintenance of appropriate institutions. Such structures do not emerge by chance, but arise from opportunity, political will and the continued efforts and commitment of many people over long periods. Suitable buildings, laboratories and state-of-the-art equipment are obviously necessary, but hardware alone is of little value in the absence of a vibrant research culture. The key characteristics of the latter are intellectual foment, open debate and a body of wisdom and knowledge about the particular subject area. Rolf Zinkernagel and 1 played a part in triggering a paradigm shift in the understanding of T cell recognition, a contribution recognized by the 1996 Nobel Prize for Physiology or Medicine. In our Nobel lectures, we both discussed briefly why it was that the John Curtin School of Medical Research (JCSMR) of 1973-75 provided a milieu that facilitated the emergence of the underlying experiments and ideas. My intention here is to discuss in more detail the scientific lineages that put this physical and intellectual environment in place, focusing particularly on the influence of Sir Frank Macfarlane (Sir Mac) Burnet as we celebrate his centenary year.
Publisher: American Society for Microbiology
Date: 04-2003
DOI: 10.1128/JVI.77.7.4231-4236.2003
Abstract: Single-envelope human immunodeficiency virus (HIV) vaccines have been studied for more than a decade, with some successes in homologous challenge experiments in nonhuman primates but with no clear successes in clinical trials. To gain insight into the breadth of the immunity elicited by such vaccines, we have dissected the T-helper cell response of C57BL/6 mice to an in idual, molecularly cloned envelope protein. Here, we report that T-helper cells responsive to HIV type 1 1035 envelope are very highly restricted in C57BL/6 animals: seven different hybridomas recovered from five separate mice recognized the same peptide, PKVSFEPIPIHYCAP, located in the C2 region of gp120. Three of these hybridomas were tested on a natural variant of the peptide but failed to respond. A more extensive analysis of whole splenic populations from other C57BL/6 mice immunized with the 1035 envelope reproducibly confirmed that the gp120-specific T-helper response was almost exclusively focused on a single epitope. We conclude that single-envelope vaccines may frequently fail to provoke an immune response sufficiently erse to recognize variant sequences among circulating HIV. The results encourage the inclusion of more than one envelope in future vaccines to enhance the potential ersity and respective surveillance capacities of responding T-helper cell populations.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-06-2007
Abstract: The rapid recall of influenza virus-specific CD8 + T cell effector function is protective, although our understanding of T cell memory remains incomplete. Recent debate has focused particularly on the CD62L lymph node homing receptor. The present analysis shows that although functional memory can be established from both CD62L hi and CD62L lo CD8 + T cell subsets soon after initial encounter between naïve precursors and antigen, the optimal precursors are CD8 + CD44 hi CD25 lo immune lymphocytes isolated from draining lymph nodes on day 3.5 after influenza virus infection. Analysis of primed T cells at different times after challenge indicates that the capacity to transfer memory is diminished at the peak of the primary cytotoxic T lymphocyte response, challenging speculations that the transition to memory first requires full differentiation to effector status. It seems that location rather than CD62Lhi/lo phenotype may be the more profitable focus for further dissection of the early establishment of T cell memory.
Publisher: Mary Ann Liebert Inc
Date: 09-2008
Abstract: Granzyme (grz) AB(-/-) H2(b) mice generate numerically normal cytotoxic T lymphocyte (CTL) responses to the prominent influenza A virus D(b) NP(366) and D(b) PA(224) epitopes and terminate the infectious process in the pneumonic lung with the same kinetics as the WT controls. Though grz B protein expression is fully compromised, there is only a partial effect on the level of CTL activity measured in a classical, short-term (51)Cr release assay. Single-cell polymerase chain reaction (PCR) analysis of both highly activated effector and "resting" memory CD8(+) T cells from influenza A virus-infected grzAB(-/-) mice showed a high prevalence of grzK mRNA(+) expression in tetramer (tet)(+) CTLs as was found in WT mice. However, a marked reduction in cytotoxicity present in the primary splenic CTLs of grzAB(-/-) mice correlated with decreased grzK expression, as measured by real-time PCR. This suggests that grzK plays an important role in CD8(+) T-cell cytotoxicity both in the presence and absence of grzA and B.
Publisher: Springer Science and Business Media LLC
Date: 07-2009
Publisher: Elsevier BV
Date: 07-1971
DOI: 10.1016/0021-9975(71)90020-X
Abstract: We demonstrate a method for the high temperature fabrication of porous, nanostructured yttria-stabilized-zirconia (YSZ, 8 mol% yttria - 92 mol% zirconia) scaffolds with tunable specific surface areas up to 80 m
Publisher: Wiley
Date: 07-2002
DOI: 10.1034/J.1600-065X.2002.18505.X
Abstract: The vertebrate immune system has evolved to deal with parasitic life forms, so it is hardly surprising that experiments with pathogens have proved illuminating for immunology. Those of us who have worked for years with infectious processes are acutely conscious that we do little more than probe the vast 'experiment of nature.' There is no place for doctrinaire rigidity in this extraordinarily complex area of biology. Though we have obviously tried to do rational experiments, much of the novelty that has been brought in to immunology from the analysis of the virus-specific host response has, in a very real sense, been the product of what we now call 'discovery science'. The following relates some of the research that I was involved in personally and attempts to put it in the context of both the history of the field and the events of the time. Virus infections, particularly HIV, pose enormous challenges for the future. It is generally helpful to know a little of what went before.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-12-2006
Abstract: Public responses where identical T cell receptors (TCRs) are clonally dominant and shared between different in iduals are a common characteristic of CD8 + T cell-mediated immunity. Focusing on TCR sharing, we analyzed ≈3,400 TCR β chains (TCRβs) from mouse CD8 + T cells responding to the influenza A virus D b NP 366 and D b PA 224 epitopes. Both the “public” D b NP 366 -specific and “private” D b PA 224 -specific TCR repertoires contain a high proportion (≈36%) of shared TCRβs, although the numbers of mice sharing TCRβs in each repertoire varies greatly. Sharing of both the TCRβ amino acid and TCRβ nucleotide sequence was negatively correlated with the prevalence of random nucleotide additions in the sequence. However, the extent of TCRβ amino acid sequence sharing among mice was strongly correlated with the level of ersity in the encoding nucleotide sequences, suggesting that a key feature of public TCRs is that they can be made in a variety of ways. Using a computer simulation of random V(D)J recombination, we estimated the relative production frequencies and variety of production mechanisms for TCRβ sequences and found strong correlations with the sharing of both TCRβ amino acid sequences and TCRβ nucleotide sequences. The overall conclusion is that “convergent recombination,” rather than a bias in recombination or subsequent selection, provides the mechanistic basis for TCR sharing between in iduals responding to identical peptide plus MHC class I glycoprotein complexes.
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1016/S1074-7613(03)00087-6
Abstract: The spectrum of TCR V beta usage is compared for primary and recall CD8(+)D(b)PA(224)(+) T cell responses in mice with influenza pneumonia. Single-cell RT-PCR established that the same clonotypes were present in the lymphoid tissue and in the virus-infected lung. Longitudinal analysis indicated that the memory TCR repertoire reflects the primary response, with no decrease in ersity prior to (or after) secondary challenge. The re-engagement of memory T cells looked to be stochastic in this localized, transient infection. Analysis of clonotypes from the blood, spleen, regional lymph nodes, bone marrow, lung, and liver over a 200 day interval showed no evidence of selective localization or loss. The long-term distribution of memory T cells seemed to be essentially random.
Publisher: Public Library of Science (PLoS)
Date: 21-03-2012
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-04-2012
DOI: 10.1126/SCITRANSLMED.3003647
Abstract: CD8 + T cell ersity may be more important than T cell abundance in limiting the negative consequences of cytomegalovirus persistence.
Publisher: Elsevier BV
Date: 1982
DOI: 10.1016/0165-5728(82)90062-5
Abstract: Virus may be recovered from various areas of the central nervous system (CNS) of mice for as long as 11 days after inoculation of herpes simplex virus type 1 (HSV-1) into the lip. The probability of isolation from any particular region of the CNS seems to be a function of the distance of that area from the root-entry zone of the trigeminal nerve. It is also mouse strain-dependent, with much more extensive evidence of brain infection being found in BALB/c and C3H rather than C57BL/6 mice, in which it is limited to the pons. The virus could not be isolated from the CNS of BALB/c mice after 10 days, though HSV-1 is readily recovered from the trigeminal ganglia at least through day 38. Significant concentrations of HSV-1-specific immunoglobulin (Ig) were demonstrated consistently in cerebrospinal fluid (CSF) from day 12 after exposure to virus. The persistence of relatively high concentrations of IgM in the CSF indicates that much of this antibody may be synthesized locally in the brain.
Publisher: Elsevier BV
Date: 03-1982
DOI: 10.1016/0008-8749(82)90103-4
Abstract: ATP is an essential constitutive regulator of cardiac ryanodine receptors (RyR2), enabling small changes in cytosolic Ca
Publisher: Wiley
Date: 02-2007
Abstract: The potent innate cytokines IL-12 and IL-18 are considered to be important antigen-independent mediators of IFN-gamma production by NK cells and T lymphocytes. The present analysis addresses the physiological role of IL-12 and IL-18 in the generation of virus-specific CD8+ T cells. Both wt C57BL/6J (B6) mice and mice with disrupted IL-12p40 (IL-12p40(-/-)) or IL-18 (IL-18(-/-)) genes were infected with an influenza A virus and the characteristics of the resultant epitope-specific CD8+ T cell responses were compared. While IL-12 appeared to have no notable effect on either virus growth or on CD8+ T cell response profiles, the absence of IL-18 was associated with delayed virus clearance from the lung and, despite normal numbers, a significantly reduced production of IFN-gamma, TNF-alpha, and IL-2 by epitope-specific CD8+ T cells. While this cytokine phenotype was broadly maintained in IL-12p40/IL-18 double-knockout mice, no evidence was seen for any additive effect. Together, our results suggest that IL-18, but not IL-12, induces optimal, antigen-specific production of key cytokines by CD8+ T cells for the efficient clearance of influenza virus from the lungs of infected mice.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.EXPHEM.2004.12.006
Abstract: To quantify the immune response of WASP- mice to three different pathogens: influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis. Primary and secondary T-cell responses to influenza A virus were quantified via tetramer assays. Viral clearance from lung was also measured. Lethality of intranasal inoculation with luminescent S. pneumoniae was assessed by dose escalation and direct luminescence imaging. After intravenous inoculation with M. bovis, residual mycobacteria in lung, liver, and spleen were measured by standard culture methods. The reduced secondary T-cell response to influenza A virus correlates with a relative but not absolute loss of splenic T and B cells similar to that seen in clinical Wiskott-Aldrich Syndrome (WAS), and slower clearance of virus from lung. The reduced magnitude of the secondary T-cell response correlates with a progressive loss of influenza-specific T cells after primary inoculation. WASP- mice show an increased susceptibility to lethal pneumonia after intranasal inoculation with S. pneumoniae, which is among the most frequent causes of clinical complications in WAS patients. WASP- mice clear M. bovis bacille Calmette-Guerin (BCG) more slowly from lung, liver, and spleen. Bone marrow-derived macrophages, however, show normal ex vivo cytokine secretion in response to M. bovis. These results demonstrate that WASP- mice are functionally immunodeficient in regard to three different pathogens, and provide relevant end points for the study of treatment modalities in this model. They also suggest a specific physiologic mechanism, failure to accumulate memory T cells, for at least one of the defective immune responses.
Publisher: Springer Science and Business Media LLC
Date: 03-1975
DOI: 10.1038/254269A0
Publisher: American Society of Hematology
Date: 11-2003
DOI: 10.1182/BLOOD-2002-11-3489
Abstract: The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP— animals that received transplants of mixtures of wild type (WT) and WASP— bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP— mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP— bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP— recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell–receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.
Publisher: Springer Science and Business Media LLC
Date: 10-2010
DOI: 10.1038/NI1010-875
Abstract: The Nobel Prizes will be announced at the beginning of October. Is there a possibility that immunology might make the list?
Publisher: American Physiological Society
Date: 04-2013
DOI: 10.1152/AJPLUNG.00343.2012
Abstract: During influenza virus infection, it is unclear how much alveolar cell loss can be tolerated before the host succumbs to the disease. We sought to define relevant correlates of disease severity in the mouse influenza model, hypothesizing that a susceptibility threshold exists for alveolar epithelial cell loss. We compared lung pathology, virus spread, alveolar epithelial cell depletion, arterial blood oxygenation, physiological responses measured by unrestrained plethysmography, and oxygen consumption and carbon dioxide production by gas analysis in mice at intervals after infection with virus strains and doses that cause mild (x31) or severe (PR/8) influenza. Both mild and severe infections showed similar degrees of lung damage and virus dissemination until day 6 after inoculation but erged in survival outcomes from day 9. Day 6 PR/8-infected mice had normal respiratory and gas exchange functions with 10% type I cell loss. However, day 10 PR/8-infected mice had 40% type I cell loss with a concomitant drastic decreases in tidal and minute volumes, V̇o 2 , V̇co 2 , and arterial blood oxygenation, compared with a maximum 3% type I cell loss for x31 on day 10 when they recovered body weight and respiratory functions. Alterations in breaths per minute, expiratory time, and metabolic rate were observed in both infections. A threshold for maintenance of proper respiratory function appears to be crossed once 10% of alveolar type I cells are lost. These data indicate that lethality in influenza virus infection is a matter of degree rather than quality.
Publisher: Elsevier BV
Date: 06-1987
DOI: 10.1016/0008-8749(87)90259-0
Abstract: The induction of severe inflammatory process and fatal neurological disease by transfer of lymphocytic choriomeningitis virus (LCMV)-immune T cells into cyclophosphamide (Cy)-suppressed LCMV-infected mice is greatly inhibited by treatment of these recipients with antibody to the asialo GM1 ganglioside (anti-ASGM1). Examination of cytotoxic activity in lymphoid tissue of the Cy-suppressed recipients at 72 hr after cell transfer revealed that anti-ASGM1 treatment prevented the development of the cytotoxic T lymphocyte (CTL) response, even though the dose of antibody used did not significantly decrease CTL generation in unsuppressed mice. Abrogation of CTL activity was also observed following antibody treatment of NK-deficient (bg/bg) Cy-suppressed recipients, indicating that the anti-ASGM1 was unlikely to be operating via removal of NK cells that are in some way involved in the development of the CTL response. The possibility that anti-ASGM1 may act directly on T cells should be considered in all protocols involving the use of this reagent in immunosuppressed mice.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2006
DOI: 10.1038/NI1343
Abstract: The continued westward dissemination of H5N1 influenza A viruses in avian populations and the nearly 50% mortality rate of humans infected with H5N1 are a source of great international concern. A mutant H5N1 virus with the capability to spread rapidly between humans could cause a global catastrophe. Governments have reacted by developing national response plans, stockpiling antiviral drugs and speeding up the development and approval of vaccines. Here we summarize what is known about the interaction between influenza A viruses and the mammalian host response, specifically emphasizing issues that might be of interest to the broader immunology community.
Publisher: Elsevier BV
Date: 10-1971
DOI: 10.1016/0021-9975(71)90080-6
Abstract: Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals. This phospho-regulatory circuit is engaged by cancer therapeutics, such as rigosertib and paclitaxel/Taxol, that activate JNK through mitotic and oxidative stress as well as by physiological regulators of the JNK cascade and may function as a signaling checkpoint to suppress the Ras pathway during conditions of cellular stress.
Publisher: Elsevier BV
Date: 11-1981
DOI: 10.1016/0008-8749(81)90049-6
Abstract: To examine the extent to which inter-regional differences in fast-food concentrations account for variations in all-cause mortality and acute coronary syndromes throughout Ontario, Canada. Nine distinct fast-food chains were selected based on top sales data in 2001. The per capita rate of fast-food outlets per region was calculated for each of 380 regions throughout Ontario. Outcome measures, obtained using 2001 vital statistics data and hospital discharge abstracts, included regional per capita mortality rates and acute coronary syndrome hospitalization rates head trauma served as a comparator. All regional outcomes were adjusted for age, gender, and socio-economic status, and were analyzed as continuous and rank-ordered variables as compared with the provincial average. Mortality and admissions for acute coronary syndromes were higher in regions with greater numbers of fast-food services after adjustment for risk. Risk-adjusted outcomes among regions intensive in fast-food services were more likely to be high outliers for both mortality (Adjusted Odds Ratio (OR): 2.52, 95% confidence intervals (CI): 1.54 - 4.13, p < 0.001) and acute coronary hospitalizations (Adjusted OR: 2.62, 95% CI 1.42 - 3.59, p < 0.001) compared to regions with low fast-food service intensity. There was no relationship between the concentration of fast-food outlets and risk-adjusted head-trauma hospitalization rates. Inter-regional cardiac outcome disparities throughout Ontario were partially explained by fast-food service intensity. Such findings emphasize the need to target health promotion and prevention initiatives to highest-risk communities.
Publisher: S. Karger AG
Date: 1975
DOI: 10.1159/000162746
Publisher: Proceedings of the National Academy of Sciences
Date: 23-05-2011
Abstract: Pathogen-specific responses are characterized by preferred profiles of peptide+class I MHC (pMHCI) glycoprotein-specific T-cell receptor (TCR) Variable (V)-region use. How TCRV-region bias impacts TCRαβ heterodimer selection and resultant ersity is unclear. The D b PA 224 –specific TCR repertoire in influenza A virus-infected C57BL/6J (B6) mice exhibits a preferred TCRV-region bias toward the TRBV29 gene segment and an optimal complementarity determining region (CDR3) β-length of 6 aa. Despite these restrictions, D b PA 224 -specific BV29 + T cells use a wide array of unique CDR3β sequences. Structural characterization of a single, TRBV29 + D b P A224 -specific TCRαβ-pMHCI complex demonstrated that CDR3α amino acid side chains made specific peptide interactions, but the CDR3β main chain exclusively contacted peptides. Thus, length but not amino acid sequence was key for recognition and flexibility in Vβ-region use. In support of this hypothesis, retrovirus expression of the D b PA 224 -specific TCRVα-chain was used to constrain pairing within a naive/immune epitope-specific repertoire. The retrogenic TCRVα paired with a ersity of CDR3βs in the context of a preferred TCRVβ spectrum. Overall, these data provide an explanation for the combination of TCRV region bias and ersity within selected repertoires, even as they maintain exquisite pMHCI specificity.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-12-2013
Abstract: A unique avian-origin H7N9 influenza virus caused 134 human infections with 44 deaths. The host factors contributing to moderate vs. severe disease are not clear. Here, we show that H7N9 severity was associated with a higher level of cytokines/chemokines. We demonstrate that the cytokines in the infected lung were 100- to 1,000-fold higher than those in the plasma. Furthermore, we found that the IFN-induced transmembrane protein-3 (IFITM3) C/C genotype was associated with severe clinical outcome, as reflected by reduced time in seeking medical aid more rapid progression to acute respiratory distress syndrome and higher viral load, cytokine/chemokine levels, and mortality rate. Overall, our data suggest that the IFITM3 genotype is a primary driver of the observed differences in clinical outcome after H7N9 infection.
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0952-7915(97)80098-2
Abstract: Virus infections cause a much more profound perturbation of the lymphoid tissue than can be accounted for by the exigencies of the antigen-specific response. The extent of this 'immunological dissonance' is seen most dramatically in mice infected with a persistent gamma-herpesvirus, MHV-68. A profile of massive, continuing proliferation of both T and B cells in the lymph nodes and spleen leads to a dramatic increase in the prevalence of a CD62Llow CD8+ T cell subset in the blood, a pattern first detected two to three weeks after intranasal exposure to the inducing virus. This syndrome, which seems identical to human infectious mononucleosis (IM), persists for a further month or more. Part of the IM-like phase of MHV-68 infection reflects the selective expansion of Vbeta4+ CD8+ T cells, with the Vbeta4 effect being apparent for several different MHC class I H-2 types but not in mice that are deficient in MHC class II glycoprotein expression. Depleting CD4(+) T helper cells in MHV-68-infected mice leads to the decreased proliferation of the CD8+ T cells in the spleen and fewer CD62Llow CD8+ T lymphocytes than would be expected in peripheral blood, but fails to diminish the prominence of the V4beta+ CD8+ population. The results so far of this unique experimental mouse model of IM suggest that both cytokine-mediated effects and a viral superantigen are operating to promote the dramatic expansion and persistence of activated CD8+ T cells in the vascular compartment.
Publisher: Elsevier BV
Date: 09-1981
DOI: 10.1016/0165-5728(81)90027-8
Abstract: Mice may be protected from the invariably fatal consequences of intracerebral (i.c.) inoculation of A/WSN influnza virus by intravenous injection with 0.5 mg of virus-specific monoclonal anti-hemagglutinin antibody given 2 days after i.c. challenge. The integrity of the blood-cerebrospinal fluid (CSF) barrier in such mice has been examined by comparing specific immunoglobulin (Ig) titers in serum and CSF. It seems that the process of virus growth results directly in substantial breakdown of the blood-CSF barrier at some time between 63 and 96 h after i.c. exposure to virus. The exogenously administered, virus-specific monoclonal antibody is not obviously involved either in abrogating the integrity of this physiological barrier system or in promoting inflammation. In fact, higher Ig titers are found in CSF for an antibody that does not bind to the virus. This presumably reflects the fact tht virus-infected cells in the central nervous system are adsorbing specific Ig from the CSF.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41467-021-23018-X
Abstract: How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal s les from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 + or CD4 + T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-02-2000
Abstract: Mice that lack CD4 + T cells remain clinically normal for more than 60 days after respiratory challenge with the murine γ-herpesvirus 68 (γHV-68), then develop symptoms of a progressive wasting disease. The γHV-68-specific CD8 + T cells that persist in these I-A b−/− mice are unable to prevent continued, but relatively low level, virus replication. Postexposure challenge with recombinant vaccinia viruses expressing γHV-68 lytic cycle epitopes massively increased the magnitude of the γHV-68-specific CD8 + population detectable by staining with tetrameric complexes of MHC class I glycoprotein + peptide, or by interferon-γ production subsequent to in vitro restimulation with peptide. The boosting effect was comparable for γHV-68-infected I-A b−/− and I-A b+/+ mice within 7 days of challenge, and took more than 110 days to return to prevaccination levels in the I-A b+/+ controls. Although the life-span of the I-A b−/− mice was significantly increased, there was no effect on long-term survival. A further boost with a recombinant influenza A virus failed to improve the situation. Onset of weight loss was associated with a decline in γHV-68-specific CD8 + T cell numbers, though it is not clear whether this was a cause or an effect of the underlying pathology. Even very high levels of virus-specific CD8 + T cells thus provide only transient protection against the uniformly lethal consequences of γHV-68 infection under conditions of CD4 + T cell deficiency.
Publisher: Portland Press Ltd.
Date: 08-1997
Abstract: The discovery of the molecular nature of T cell-mediated immunity is reviewed in a historical context. Current approaches to understanding virus-induced inflammatory processes are described.
Publisher: Elsevier BV
Date: 02-1985
DOI: 10.1016/0008-8749(85)90204-7
Abstract: Adoptively transferred immune spleen cells induce fatal neurological disease in cyclophosphamide-suppressed recipients injected intracerebrally (ic) with a large, but not small, dose of neurotropic lymphocytic choriomeningitis (LCM) virus. The elimination of virus from brain in the latter group, which survives without developing symptoms, depends upon the presence of Lyt 2+ lymphocytes. However removal of Lyt 2+ subset which is cytotoxic in vitro does not diminish the severity of the inflammatory process in vivo, though the onset of clinical disease is delayed in mice given Lyt 2-depleted populations and a larger ic dose of virus. The present findings are consistent with the idea that fatal LCM results from acute, synchronous damage to key functional cells in the central nervous system by virus-immune Lyt 2+, lymphocytes. Even so, if the number of virus-infected CNS cells is still relatively small at the time of T cell invasion, neurological symptoms are not recognized and the mice survive.
Publisher: American Society for Microbiology
Date: 04-2005
DOI: 10.1128/JVI.79.7.4329-4339.2005
Abstract: The extent to which CD8 + T cells specific for other antigens expand to compensate for the mutational loss of the prominent D b NP 366 and D b PA 224 epitopes has been investigated using H1N1 and H3N2 influenza A viruses modified by reverse genetics. Significantly increased numbers of CD8 + K b PB1 703 + , CD8 + K b NS2 114 + , and CD8 + D b PB1-F2 62 + T cells were found in the spleen and in the inflammatory population recovered by bronchoalveolar lavage from mice that were first given the −NP−PA H1N1 virus intraperitoneally and then challenged intranasally with the homologous H3N2 virus. The effect was less consistent when this prime-boost protocol was reversed. Also, though the quality of the response measured by cytokine staining showed some evidence of modification when these minor CD8 + -T-cell populations were forced to play a more prominent part, the effects were relatively small and no consistent pattern emerged. The magnitude of the enhanced clonal expansion following secondary challenge suggested that the prime-boost with the −NP−PA viruses gave a response overall that was little different in magnitude from that following comparable exposure to the unmanipulated viruses. This was indeed shown to be the case when the total response was measured by ELISPOT analysis with virus-infected cells as stimulators. More surprisingly, the same effect was seen following primary challenge, though in idual analysis of the CD8 + K b PB1 703 + , CD8 + K b NS2 114 + , and CD8 + D b PB1-F2 62 + sets gave no indication of compensatory expansion. A possible explanation is that novel, as yet undetected epitopes emerge following primary exposure to the −NP−PA deletion viruses. These findings have implications for both natural infections and vaccines.
Publisher: Elsevier BV
Date: 02-1982
DOI: 10.1016/0008-8749(82)90198-8
Abstract: Successful endodontic treatment requires a significant knowledge of root canal anatomy. The aim of this study was to evaluate the root and root canal number of permanent teeth among the Moscow population using cone-beam computed tomography (CBCT) scanning. 300 CBCT images of subjects were analyzed to study the anatomy of roots and root canal system of each tooth. The collected data were analyzed using IBM SPSS statistics software 22.0 version. The maxillary incisors and canines had one root with one canal in 100%. Maxillary premolars had one root with one or two canals and two roots with two canals, while mandibular premolars were single-rooted with one or two canals. Maxillary first and second molar had three separated roots, and the prevalence of four canals was more often in first molars. Mandibular molars had two roots with different number of canals. The root canal system varies greatly among populations and even in different in iduals within the same population thus, using CBCT scanning is an effective technique in investigating the root canal system.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-12-1998
Abstract: The murine γ-herpesvirus 68 replicates in epithelial sites after intranasal challenge, then persists in various cell types, including B lymphocytes. Mice that lack CD4 + T cells (I-A b−/− ) control the acute infection, but suffer an ultimately lethal recrudescence of lytic viral replication in the respiratory tract. The consequences of CD4 + T cell deficiency for the generation and maintenance of murine γ-herpesvirus 68-specific CD8 + set now have been analyzed by direct staining with viral peptides bound to major histocompatibility complex class I tetramers and by a spectrum of functional assays. Both acutely and during viral reactivation, the CD8 + T cell responses in the I-A b−/− group were no less substantial than in the I-A b+/+ controls. Indeed, virus-specific CD8 + T cell numbers were increased in the lymphoid tissue of clinically compromised I-A b−/− mice, although relatively few of the potential cytotoxic T lymphocyte effectors were recruited back to the site of pathology in the lung. Thus the viral reactivation that occurs in the absence of CD4 + T cells was not associated with any exhaustion of the virus-specific cytotoxic T lymphocyte response. It seems that CD8 + T cells alone are insufficient to maintain long-term control of this persistent γ-herpesvirus.
Publisher: Elsevier BV
Date: 04-1984
DOI: 10.1016/0008-8749(84)90112-6
Abstract: Limiting dilution culture conditions were established which allowed the differentiation and quantitation of influenza-specific cytotoxic T-cell precursors (CTL.Ps) from naive mouse spleen and thymus. One in 49,000 nucleated spleen cells and 1 in 40,000 thymocytes responded to stimulation with influenza-infected, anti-Thy 1.2 and complement-treated spleen cells, in the presence of ConA-stimulated cell supernatant, with the production of cytotoxic effector cells. These frequencies are 4- to 15-fold higher than those for influenza-responsive B cells in the relevant lymphoid compartments, and it is argued that major quantitative discrepancies may exist in the sizes of the B- and CTL-receptor repertoires.
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S1074-7613(00)80573-7
Abstract: Virus-specific CD8+ effector T cells (eCTL) are enriched in the lungs of mice with primary influenza pneumonia, though later detection of memory T cells (mCTL) in the mediastinal lymph nodes (MLN) or spleen by peptide-based staining protocols is at the limits of flow cytometric analysis. Respiratory challenge with an H3N2 virus months after H1N1 priming induces a massive recall response, which reduces virus titers 2-3 days earlier than in nave controls. Influenza-specific mCTL produce interferon-gamma within 6 hr, but still take 4-5 days to localize to the infected respiratory tract. The delay reflects that the recall response develops first in the MLN, which contains relatively few mCTL. The response to a subdominant epitope is less obvious after secondary challenge.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 08-05-2001
Abstract: The CD8 + T cell diaspora has been analyzed after secondary challenge with an influenza A virus that replicates only in the respiratory tract. Numbers of D b NP 366 - and D b PA 224 -specific CD8 + T cells were measured by tetramer staining at the end of the recall response, then followed sequentially in the lung, lymph nodes, spleen, blood, and other organs. The extent of clonal expansion did not reflect the sizes of the preexisting memory T cell pools. Although the high-frequency CD8 + tetramer + populations in the pneumonic lung and mediastinal lymph nodes fell rapidly from peak values, the “whole mouse” virus-specific CD8 + T cell counts decreased only 2-fold over the 4 weeks after infection, then subsided at a fairly steady rate to reach a plateau at about 2 months. The largest numbers were found throughout in the spleen, then the bone marrow. The CD8 + D b NP 366 + and CD8 + D b PA 224 + sets remained significantly enlarged for at least 4 months, declining at equivalent rates while retaining the nucleoprotein acid polymerase immunodominance hierarchy characteristic of the earlier antigen-driven phase. Lowest levels of the CD69 “activation marker” were detected consistently on virus-specific CD8 + T cells in the blood, then the spleen. Those in the bone marrow and liver were intermediate, and CD69 hi T cells were very prominent in the regional lymph nodes and the nasal-associated lymphoid tissue. Any population of “resting” CD8 + memory T cells is thus phenotypically heterogeneous, widely dispersed, and subject to broad homeostatic and local environmental effects irrespective of epitope specificity or magnitude.
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0165-5728(94)90076-0
Abstract: The invariably fatal immunopathological disease that follows intracerebral injection of CBA/Ca (H-2k) mice with 1000 PFU of lymphocytic choriomeningitis virus (LCMV) generally fails to develop in congenic mice transgenic for a V beta 8.1D beta 2J beta 2.3C beta 2 T cell receptor (TCR) gene. The majority of these LCMV-infected TCR-transgenic mice show a substantial meningitis of delayed onset, that resolves without causing any obvious clinical impairment. This inflammatory process depends on the involvement of V beta 8+ T cells, but does not require the participation of the CD4+ subset. The cytotoxic effectors that develop in both the transgenic mice and the CBA/Ca controls are lytic for target cells infected with a vaccinia construct expressing genes encoding the putative polymerase protein of LCMV. Limiting the available TCR repertoire to lymphocytes with a single V beta phenotype (not required for the generation of potent effectors in wild-type mice) thus modifies the development of the lethal neuropathology characteristic of LCMV infection, although the CD8+ cytotoxic T lymphocyte response is not greatly compromised.
Publisher: Annual Reviews
Date: 04-2000
DOI: 10.1146/ANNUREV.IMMUNOL.18.1.561
Abstract: The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen-specific CD8 + T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8 + T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values. The levels are such that the virus-specific CD8 + set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer + CD8 + T cells during the acute and memory phases of the host response to viruses. Dissection of the phenotypic, functional, and molecular ersity of CD8 + T cell populations has been greatly facilitated. It is hoped it will also soon be possible to analyze CD4 + T cell populations in this way. Though these are early days and there is an enormous amount to be done, our perceptions of the shape of virus-specific cell-mediated immunity are changing rapidly.
Publisher: Springer Science and Business Media LLC
Date: 11-2003
DOI: 10.1038/NI1103-1043
Publisher: Elsevier BV
Date: 10-1971
DOI: 10.1016/0022-510X(71)90091-8
Abstract: Functional assessment may represent a valuable addition to postpartum depression screening, providing a more thorough characterization of the mother's health and quality of life. To the authors' knowledge, this analysis represents the first examination of postpartum maternal functioning, as measured by a patient-centered validated tool aimed at ascertainment of functional status explicitly, and its clinical and sociodemographic correlates. A total of 189 women recruited from a large, urban women's hospital in the northeastern United States who both (1) screened positive for depression between 4 and 6 weeks postpartum and (2) completed a subsequent home (baseline) visit between October 1, 2008, and September 4, 2009, were included in this analysis. Multiple linear regression was conducted to ascertain which clinical and sociodemographic variables were independently associated with maternal functioning. The multivariate analysis revealed independent associations between bipolar status, atypical depression, depression score (17-item Hamilton Rating Scale for Depression), and insurance type with postpartum maternal functioning. The beta coefficient for bipolar status indicates that on average we would expect those with bipolar disorder to have maternal functioning scores that are 5.6 points less than those without bipolar disorder. Healthcare providers treating postpartum women with complicating mental health conditions should be cognizant of the potential ramifications on maternal functioning. Impaired functioning in the maternal role is likely to impact child development, although the precise nature of this relationship is yet to be elucidated.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-04-2009
Abstract: Antigen expressed as MHC Class I glycoprotein (pMHCI) complexes on dendritic cells is the primary driver of CD8 + T cell clonal expansion and differentiation. As we seek to define the molecular differences between acutely stimulated cytotoxic T lymphocyte (CTL) effectors and long-lived memory T cells, it is essential that we understand the duration of in vivo pMHCI persistence. Although infectious influenza A virus is readily cleared by mammalian hosts, that does not necessarily mean that all influenza antigen is totally eliminated. An exhaustive series of carefully controlled adoptive transfer experiments using 3 different carboxy fluorescein diacetate succinimidyl ester–labeled T cell receptor–transgenic CTL populations and a spectrum of genetically engineered and wild-type influenza A viruses provided no evidence for pMHCI persistence over the 30–60-d interval after virus challenge. Molecular profiles identified in antigen-specific T cells at this time may thus be considered to reflect established immunologic memory and not recent CTL activation from a persistent pMHCI pool.
Publisher: Elsevier BV
Date: 05-1994
Publisher: Springer Science and Business Media LLC
Date: 13-05-2015
DOI: 10.1038/NCOMMS7833
Abstract: The avian origin A/H7N9 influenza virus causes high admission rates ( %) and mortality ( %), with ultimately favourable outcomes ranging from rapid recovery to prolonged hospitalization. Using a multicolour assay for monitoring adaptive and innate immunity, here we dissect the kinetic emergence of different effector mechanisms across the spectrum of H7N9 disease and recovery. We find that a ersity of response mechanisms contribute to resolution and survival. Patients discharged within 2–3 weeks have early prominent H7N9-specific CD8 + T-cell responses, while in iduals with prolonged hospital stays have late recruitment of CD8 + /CD4 + T cells and antibodies simultaneously (recovery by week 4), augmented even later by prominent NK cell responses (recovery days). In contrast, those who succumbed have minimal influenza-specific immunity and little evidence of T-cell activation. Our study illustrates the importance of robust CD8 + T-cell memory for protection against severe influenza disease caused by newly emerging influenza A viruses.
Publisher: Wiley
Date: 25-09-2019
Abstract: The mechanistic basis of memory T-cell development is poorly defined. Phenotypic markers that define precursors at effector stages have been characterized for acute systemic infections with high antigen load. We asked whether such markers can identify memory precursors from early effectors (d6) to late memory (>d500) for two immunodominant CD8(+) responses during the course of a localized low-load influenza infection in mice. CD8(+) T cells stained with the D(b) NP(366) and D(b) PA(224) tetramers were characterized as IL-7Rα(hi) , IL-7Rα(hi) CD62L(hi) or IL-7Rα(hi) KLRG1(lo) . While the D(b) NP(366) - and D(b) PA(224) -specific responses were comparable in size, decay kinetics and memory precursor frequency, their expansion characteristics differed. This correlated with a ergence in the IL-7Rα(hi) , IL-7Rα(hi) CD62L(hi) and IL-7Rα(hi) KLRG1(lo) phenotypes on effector, but not naïve, CD8(+) populations. That effect was abrogated by priming with viruses engineered to present equivalent levels of NP(366) and PA(224) peptides, indicating that memory phenotypes reflect early antigenic experience rather than memory potential. Thus, the IL-7Rα(hi) KLRG1(lo) phenotype had a poor predictive value in identifying memory precursors in the spleen and at the site of infection. Greater consistency in influenza-specific IL-7Rα(hi) KLRG1(lo) CD8(+) T-cell numbers was found in draining lymph nodes, suggesting that this may be the preferential site for memory establishment and maintenance following localized virus infections.
Publisher: Elsevier BV
Date: 06-2009
Publisher: Springer Science and Business Media LLC
Date: 13-01-2021
Publisher: Springer Science and Business Media LLC
Date: 06-1985
DOI: 10.1007/BF00395882
Abstract: Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline. The telomere carrying the CI-HHV-6 is also prone to truncations that result in the formation of a short telomere at a novel location within the viral genome. We detected extra-chromosomal circular HHV-6 molecules, some surprisingly comprising the entire viral genome with a single fully reconstituted direct repeat region (DR) with both terminal cleavage and packaging elements (PAC1 and PAC2). Truncated CI-HHV-6 and extra-chromosomal circular molecules are likely reciprocal products that arise through excision of a telomere-loop (t-loop) formed within the CI-HHV-6 genome. In summary, we show that the CI-HHV-6 genome disrupts stability of the associated telomere and this facilitates the release of viral sequences as circular molecules, some of which have the potential to become fully functioning viruses.
Publisher: Elsevier BV
Date: 08-1993
DOI: 10.1016/0952-7915(93)90026-O
Abstract: The experimental dissection of the ways that the various cells and molecules of the immune system interact to promote virus clearance has been greatly facilitated by the availability of mice with targeted disruptions of key genes. New insights are emerging, and details of host resistance mechanisms that could only be inferred for the in vivo situation are now being clearly established.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2009
DOI: 10.1038/CLPT.2009.52
Publisher: Elsevier BV
Date: 04-1988
DOI: 10.1016/0090-1229(88)90141-9
Abstract: The Lyt2+ class I major histocompatibility complex (MHC)-restricted virus-immune T cells that induce murine lymphocytic choriomeningitis (LCM) are targeted onto radiation-resistant cells in the central nervous system of virus-infected mice. The use of appropriate bone marrow radiation chimeras as LCM virus-infected, (immunosuppressed recipients for immune T-cell transfer has established that, though bone marrow-derived cells can stimulate virus-specific cytotoxic T lymphocytes (CTL) in spleen, they do not reconstitute the barrier to T-cell recruitment from blood to cerebrospinal fluid. This is true for chimeras made up to 8 months previously, even though the inflammatory monocytes and macrophages in such chimeras are all of donor bone marrow origin. Radiation-resistant cells in the spleens of these chimeras are also still able to further stimulate virus-immune CTL. There is no requirement for H-2 compatibility between virus-immune T lymphocytes and secondarily recruited monocytes, or T cells of an inappropriate specificity. The key event in LCM immunopathology may thus be localization of T cells to the antigen-presenting endothelium in brain, leading to the secretion of mediators that promote the nonspecific recruitment of monocytes and other T cells.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.JIM.2007.09.016
Abstract: The CD8+ T cell response is important in the control of many viral and other infections. There have been many studies aimed at better understanding the influence of T cell receptor ersity on immune responses and the evolution of the T cell receptor repertoire over time and through the various stages of immune responses to infection. In recent years, there has been an increase in both the number of studies using T cell receptor data and the volume of T cell receptor data generated per study. Appropriate analytical tools are required to analyse this data. We present a robust approach to assessing the similarity between s les of the T cell receptor repertoire, which we demonstrate on published data of subsets of the influenza A virus D(b)NP366(-) and D(b)PA224(-)specific CD8+ T cell responses in mice sorted on the expression of CD62L, which is a marker distinguishing central and effector memory cells.
Publisher: Rockefeller University Press
Date: 28-07-2003
DOI: 10.1084/JEM.20022151
Abstract: The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For ex le, NP366–374/Db- and PA224–233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366–374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366–374/Db epitope, whereas only dendritic cells effectively present the PA224–233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366–374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224–233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224–233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-01-1999
Abstract: Human severe combined immunodeficiency (SCID) can be caused by defects in Janus kinase 3 (JAK3)-dependent cytokine signaling pathways. As a result, patients are at high risk of life-threatening infection. A JAK3 −/− SCID mouse model for the human disease has been used to test whether transplant with retrovirally transduced bone marrow (BM) cells (JAK3 BMT) could restore immunity to an influenza A virus. The immune responses also were compared directly with those for mice transplanted with wild-type BM (+/+ BMT). After infection, approximately 90% of the JAK3 BMT or +/+ BMT mice survived, whereas all of the JAK3 −/− mice died within 29 days. Normal levels of influenza-specific IgG were present in plasma from JAK3 BMT mice at 14 days after respiratory challenge, indicating restoration of B cell function. Influenza-specific CD4 + and CD8 + T cells were detected in the spleen and lymph nodes, and virus-specific CD8 + effectors localized to the lungs of the JAK3 BMT mice. The kinetics of the specific host response correlated with complete clearance of the virus within 2 weeks of the initial exposure. By contrast, the JAK3 −/− mice did not show any evidence of viral immunity and were unable to control this viral pneumonia. Retroviral-mediated JAK3 gene transfer thus restores erse aspects of cellular and humoral immunity and has obvious potential for human autologous BMT.
Publisher: Wiley
Date: 15-06-2010
DOI: 10.1002/IUB.351
Abstract: CD8(+) T cells are critical for protecting the body from infectious disease. To achieve this protection, CD8(+) T cells must undergo a highly involved process of differentiation that involves the activation of naïve/quiescent cells followed by robust rounds of cell ision and the acquisition of effector functions that mediate viral clearance. After the pathogen is eliminated, a small number of these cells survive into long-lived memory and maintain the capacity to respond rapidly and reacquire effector function after secondary exposure to their cognate antigen. This review focuses on how CD8(+) T cells acquire and regulate effector functions and how the capacity to produce effector molecules is maintained into memory.
Publisher: The American Association of Immunologists
Date: 12-2009
Abstract: The role of chromatin remodeling and histone posttranslational modifications and how they are integrated to control gene expression during the acquisition of cell-specific functions is poorly understood. We show here that following in vitro activation of CD4+ and CD8+ T lymphocytes, both cell types show rapid histone H3 loss at the granzyme B (gzmB) proximal promoter region. However, despite the gzmB proximal promoter being remodeled in both T cell subsets, only CD8+ T cells express high levels of gzmB and display a distinct pattern of key epigenetic marks, notably differential H3 acetylation and methylation. These data suggest that for high levels of transcription to occur a distinct set of histone modifications needs to be established in addition to histone loss at the proximal promoter of gzmB.
Publisher: American Society for Microbiology
Date: 02-2014
DOI: 10.1128/JVI.02851-13
Abstract: One question that continues to challenge influenza A research is why some strains of virus are so devastating compared to their more mild counterparts. We approached this question from an immunological perspective, investigating the CD8 + T cell response in a mouse model system comparing high- and low-pathological influenza virus infections. Our findings reveal that the early (day 0 to 5) viral titer was not the determining factor in the outcome of disease. Instead, increased numbers of antigen-specific CD8 + T cells and elevated effector function on a per-cell basis were found in the low-pathological infection and correlated with reduced illness and later-time-point (day 6 to 10) viral titer. High-pathological infection was associated with increased PD-1 expression on influenza virus-specific CD8 + T cells, and blockade of PD-L1 in vivo led to reduced virus titers and increased CD8 + T cell numbers in high- but not low-pathological infection, though T cell functionality was not restored. These data show that high-pathological acute influenza virus infection is associated with a dysregulated CD8 + T cell response, which is likely caused by the more highly inflamed airway microenvironment during the early days of infection. Therapeutic approaches specifically aimed at modulating innate airway inflammation may therefore promote efficient CD8 + T cell activity. IMPORTANCE We show that during a severe influenza virus infection, one type of immune cell, the CD8 T cell, is less abundant and less functional than in a more mild infection. This dysregulated T cell phenotype correlates with a lower rate of virus clearance in the severe infection and is partially regulated by the expression of a suppressive coreceptor called PD-1. Treatment with an antibody that blocks PD-1 improves T cell functionality and increases virus clearance.
Publisher: Elsevier BV
Date: 06-1975
DOI: 10.1016/S0140-6736(75)92610-0
Abstract: A central function of the major histo-compatibility (H) antigens may be to signal changes in self to the immune system. Virus-induced modification of strong transplantation antigens apparently results in recognition by thymus-derived lymphocytes (T cells), with subsequent clonal expansion and immune elimination of cells bearing non-self determinants. The extreme genetic polymorphism found in the major H antigen systems of higher vertebrates may reflect evolutionary pressure exerted by this immunological surveillance mechanism.
Publisher: Wiley
Date: 29-04-2009
Abstract: CTL mediate anti-viral immunity via targeted exocytosis of cytolytic granules containing perforin and members of the granzyme (grz) serine protease family. Here, we provide the first analysis of grzA protein expression by murine anti-viral CTL. During the progression of influenza A virus infection, CTL expressed two ergent cytolytic phenotypes: grzA(-)B(+) and grzA(+)B(+). CTL lacked grzA expression during the initial rounds of antigen-driven ision. High levels of grzA were expressed by influenza-specific CTL early post infection (day 6), particularly in tissues associated with the infected respiratory tract (bronchoalveolar lavage, lung). Following resolution of influenza infection, a small population of memory CTL expressed grzA. Interestingly, in idual influenza A virus-derived epitope-specific CTL expressed different levels of grzA. The grzA expression hierarchy was determined to be K(b)PB1(703)=D(b)F2(62)=K(b)NS2(114)>D(b)NP(366)=D(b)PA(224) and inversely correlated with CTL magnitude. Therefore following influenza infection, a CTL cytolytic hierarchy was established relating to the different profiles of antigen expression and relative immunodominance. Analysis of CTL grzA expression during influenza virus immunity has enabled a more detailed insight into the cytolytic mechanisms of virus elimination.
Publisher: Elsevier BV
Date: 06-1981
Publisher: Springer Science and Business Media LLC
Date: 11-1986
DOI: 10.1007/BF00395536
Abstract: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN). DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score>2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates. Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62±9 years, mean HbA1c 7.7±1.6%, diabetes duration 10±9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P=0.02), which remained significant after adjusting for the in-trial HbA1c (P=0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58-0.99], P<0.01). Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2013
DOI: 10.1038/NI.2741
Publisher: American Medical Association (AMA)
Date: 04-10-1995
Publisher: Bentham Science Publishers Ltd.
Date: 06-2005
Abstract: The prevention of HIV-1 by vaccination has proven to be a formidable task. In an ongoing endeavor to end the HIV-1 pandemic, scientists seek vaccines that will elicit quantitatively and qualitatively robust B-cell and T-cell activities. Given that cytotoxic T-lymphocytes (CTL) play a substantial role in the immunological control of immunodeficiency virus infections, this review will focus on vaccines designed to elicit HIV-1-specific CTL. Vaccine approaches using various HIV-1 proteins or specific CTL determinants, partnered with erse delivery systems and adjuvants will be discussed. Lessons from studies with other virus models (e.g. gamma herpes virus and influenza virus) will also be examined. Since CTL contribute to the success of vaccines in other model systems, an understanding of the strengths and possible limitations of these cells may be critical to future successes in the HIV-1 vaccine field.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-03-2009
Abstract: Current influenza A virus vaccines do not generate significant immunity against serologically distinct influenza A virus subtypes and would thus be ineffective in the face of a pandemic caused by a novel variant emerging from, say, a wildlife reservoir. One possible solution would be to modify these vaccines so that they prime cross-reactive CD8 + cytotoxic T lymphocytes (CTL) cell-mediated immunity directed at conserved viral epitopes. A further strategy is to use novel adjuvants, such as the immunomodulatory glycolipid α-galactosylceramide (α-GalCer). We show here that giving α-GalCer with an inactivated influenza A virus has the paradoxical effect of diminishing acute CTL immunity via natural killer T (NKT) cell-dependent expression of indoleamine 2,3-dioxygenase (IDO), an important mediator of immune suppression, while at the same time promoting the survival of long-lived memory CTL populations capable of boosting protection against heterologous influenza A virus challenge. This enhancement of memory was likely due to the α-GalCer-induced upregulation of prosurvival genes, such as bcl-2, and points to the potential of α-GalCer as an adjuvant for promoting optimal, vaccine-induced CD8 + T cell memory.
Publisher: Springer Science and Business Media LLC
Date: 05-1986
DOI: 10.1007/BF02122449
Abstract: Age-related changes in social attribution skills were assessed using the "Triangles Playing Tricks" task in 7-17 year old high functioning children with ASDs (n=41) and in typically developing (TD) children (n=58) matched on age, IQ, and sex ratio. Children with ASDs gave responses that received lower intentionality and appropriateness ratings than did TD children in both the goal-directed and theory of mind (ToM) conditions. Results remained unchanged when the effects of verbal output (i.e., number of clause produced) and verbal IQ were included as covariates in the analyses. Whereas age was highly associated with ToM performance in the TD children, this relationship was not as strong among children with ASDs. These results indicate not only a diminished tendency among high functioning children with ASDs to attribute social meaning and intentionality to ambiguous visual displays of interactive forms but also an aberrant developmental trajectory. That is, children with ASDs may fall further behind their typically developing peers in social attribution abilities as they get older.
Publisher: Elsevier BV
Date: 06-1987
DOI: 10.1016/0008-8749(87)90260-7
Abstract: Virus-immune spleen cells induce fatal immunopathology following adoptive transfer into adult C57B1/6J mice that have been infected with lymphocytic choriomeningitis virus (LCMV) and immunosuppressed with cyclophosphamide. This is accompanied by the development of potent cytotoxic T-lymphocyte (CTL) activity of donor origin in the recipient spleen. Both the capacity to trigger the acute meningitis observed at 72 hr and to generate CTL effectors in lymphoid tissue are completely abrogated by the removal of Lyt-2+ cells from the donor population. However a lower level of inflammatory process in the central nervous system may emerge, in the absence of significant CTL function in recipient spleen, by 5 days after transfer of the Lyt-2-depleted cell population. Treatment of the transferred cells with antibody to the L3T4 marker does not reduce either the severity of inflammation or the level of CTL effector function in the recipient. Thus Lyt-2+ cells are required for the acute, fatal immunopathology characteristic of LCM, but it is not clear that in a more chronic situation, they are the sole effectors capable of triggering inflammatory process in this disease.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1038/NI0109-14
Abstract: A systems biology approach provides correlates of successful vaccination, which allows a new method for measuring early vaccine efficiency and suggests hypotheses for the mechanisms that underlie immunogenicity.
Publisher: Elsevier BV
Date: 05-1981
DOI: 10.1016/0022-1759(81)90038-7
Abstract: The emergence of virus-specific cytotoxic T lymphocyte (CTL) precursors in thymus can be examined directly by stimulating thymocytes for 6 days in irradiated, virus-infected recipients. Responsiveness is a characteristic of the thymocytes themselves and does not reflect the presence of contaminating, blood-bourne T cells. Strong CTL activity may be generated earlier from thymus than from spleen or lymph node of lethally irradiated, bone marrow reconstituted mice. Also, the reconstitution of virus-immune CTL function in these peripheral lymphoid organs is thymus-dependent. Use of this simple experimental protocol offers considerable possibilities for the analysis of the role of the thymus in the ontogeny of the T cell repertoire.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-2005
Abstract: Prior analysis has characterized the clonal characteristics of effector CD8 + T cells specific for the prominent influenza A virus nucleoprotein (NP) and acid polymerase (PA) peptides presented by H2D b . Using a single-cell approach and determination of CDR3β profiles, a limited, predominantly “public” repertoire was found for CD8 + D b NP 366 + Vβ8.3 + cells, whereas erse and “private” T cell antigen receptor (TCR)β clonotypes were typical of the CD8 + D b PA 224 + Vβ7 + response. This single-cell approach has now been used to relate the contributions of particular clonotypes (or affinities) to high-avidity TCRs, as defined by binding under conditions of limiting tetramer availability. At least by the measure of CDR3β usage, no difference could be found between total and high-avidity populations in the spectrum of TCR-pMHC affinities throughout the limited, and relatively public, CD8 + D b NP 366 + Vβ8.3 + populations. Conversely, the more even (by clone size), erse, and private CD8 + D b PA 224 + Vβ7 + response was characterized by the clear partitioning of the largest T cell clones in the high-avidity compartment. These results suggest that the relatively constrained CD8 + D b NP 366 + Vβ8.3 + set utilizes a relatively narrow range of affinities, whereas the broader CD8 + D b PA 224 + Vβ7 + response is induced at a range of TCR-pMHC affinities. Thus, whereas TCR sequence (or affinity) appears to contribute substantially to the avidity profile of erse virus-specific CD8 + populations, other mechanisms may be prominent where the TCR spectrum is more limited.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-07-2000
Abstract: The γ-herpesviruses, in contrast to the α- and β-herpesviruses, are not known to inhibit antigen presentation to CD8 + cytotoxic T lymphocytes (CTLs) during lytic cycle replication. However, murine γ-herpesvirus 68 causes a chronic lytic infection in CD4 + T cell-deficient mice despite the persistence of a substantial CTL response, suggesting that CTL evasion occurs. Here we show that, distinct from host protein synthesis shutoff, γ-herpesvirus 68 down-regulates surface MHC class I expression on lytically infected fibroblasts and inhibits their recognition by antigen-specific CTLs. The viral K3 gene, encoding a zinc-finger-containing protein, dramatically reduced the half-life of nascent class I molecules and the level of surface MHC class I expression and was by itself sufficient to block antigen presentation. The homologous K3 and K5 genes of the related Kaposi's sarcoma-associated virus also inhibited antigen presentation and decreased cell surface expression of HLA class I antigens. Thus it appears that an immune evasion strategy shared by at least two γ-herpesviruses allows continued lytic infection in the face of strong CTL immunity.
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/S1074-7613(04)00021-4
Abstract: A common feature of many infections is that many pathogen-specific memory T cells become established in erse nonlymphoid tissues. A mechanism that promotes the retention and survival of the memory T cells in erse tissues has not been described. Our studies show that the collagen binding alpha1beta1 integrin, VLA-1, is expressed by the majority of influenza-specific CD8 T cells recovered from nonlymphoid tissues during both the acute and memory phases of the response. Antibody treatment or genetic deficiency of VLA-1 decreased virus-specific CTL in the lung and other nonlymphoid tissues, and increased them in the spleen. In spite of the increase in the spleen, secondary heterosubtypic immunity against flu was compromised. This suggests that VLA-1 is responsible for retaining protective memory CD8 T cells in the lung and other tissues via attachment to the extracellular matrix.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-03-2004
Abstract: The CD8 + T cell response to the immunodominant D b NP 366 epitope has been analyzed sequentially to determine the prevalence and persistence of different T cell antigen receptor (TCR)Vβ8.3 clonotypes after primary and secondary influenza virus challenge. Based on the length and amino acid sequences of the complementarity-determining region 3 of TCRβ (CDR3β) loop and associated Jβ usage, the same dominant TCRβ signatures were found in the blood, the spleen, and the site of virus-induced pathology in the infected respiratory tract. Longitudinal analysis demonstrated that TCRβ prominent in the antigen-driven phase of response persisted into memory and were again expanded after secondary challenge. A proportion of these high-frequency TCRβ expressed “public” CDR3β sequences that were detected in every mouse s led, whereas others were found more than once but were not invariably present. Analysis of N-region nucleotide ersity established that as many as 10 different nucleic acid sequences (maximum of four “nucleotypes” in any one mouse) could encode a single public TCRβ amino acid sequence. Conversely, whereas some of the unique, “private” TCRβ achieved a substantial clone size, they were always specified by a single nucleotype. Although there is a strong stochastic element in this response, the public TCRβ seem to represent a “best fit” for this immunodominant epitope, are selected preferentially from the naive TCR repertoire, and assume even greater prominence after secondary challenge.
Publisher: American Society for Microbiology
Date: 15-07-2003
DOI: 10.1128/JVI.77.14.7756-7763.2003
Abstract: The consequences for the long-term maintenance of virus-specific CD8 + -T-cell memory have been analyzed experimentally for sequential respiratory infections with readily eliminated (influenza virus) and persistent (gammaherpesvirus 68 [γHV68]) pathogens. S ling a broad range of tissue sites established that the numbers of CD8 + T cells specific for the prominent influenza virus D b NP 366 epitope were reduced by about half in mice that had been challenged 100 days previously with γHV68, though the prior presence of a large CD8 + D b NP 366 + population caused no selective defect in the γHV68-specific CD8 + K b p79 + response. Conversely, mice that had been primed and boosted to generate substantial γHV68-specific CD8 + D b p56 + populations did not show any decrease in prevalence for this set of CD8 + memory cytotoxic T lymphocytes (CTL) at 200 days after respiratory exposure to an influenza A virus. However, in both experiments, the total magnitude of the CD8 + -T-cell pool was significantly diminished in those that had been infected with γHV68 and the influenza A virus. The broader implications of these findings, especially under conditions of repeated exposure to unrelated pathogens, are explored with a mathematical model which emphasizes that the immune effector and memory “phenome” is a function of the overall infection experience of the in idual.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Wiley
Date: 1987
Abstract: The expression of Pgp-1 (Ly24) by subpopulations of thymocytes was investigated and a subpopulation of Lyt-2-/L3T4-/J11d- thymocytes was identified which contained significant numbers (80%) of Pgp-1+ cells. Among freshly isolated lymph node T cells but not cortisone-resistant thymocytes, Pgp-1 expression was heterogeneous. Stimulation of T lymphocytes with either concanavalin A or the combination of phorbol myristate acetate plus calcium ionophore resulted in increased Pgp-1 expression which was found to be regulated independently of DNA synthesis and interleukin 2 receptor expression. T cells in the cerebrospinal fluid exudate of mice infected with lymphocytic choriomeningitis virus were also found to be Pgp-1+.
Publisher: Springer Science and Business Media LLC
Date: 1983
DOI: 10.1007/BF00364291
Abstract: Serous carcinomas of the testis or para-testis are extremely rare tumors of Mullerian type. We report a case of high-grade serous papillary carcinoma of the tunica vaginalis, treated with radical orchiectomy and hemi-scrotectomy after being referred for a rapidly growing painless scrotal mass. In addition to negative testicular tumor markers, scrotal ultrasound, and conventional computerized tomography (CT) scanning, this patient's workup included a positron emission tomography (PET) scan using F-18-fluoro-deoxyglucose (FDG), demonstrating metabolically avid uptake of the disease. This patient is completing ongoing close follow up and is currently disease free at nine months post definitive treatment.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1186/JBIOL147
Publisher: Wiley
Date: 2009
Abstract: The CD8(+) T-cell response to infection involves a large initial expansion in the numbers of responding cells, accompanied by differentiation of these cells. Expression of the adhesion molecule CD62L is high on naïve cells and rapidly downregulated on the surface of the majority (approximately 90%) of cells during the 'effector' phase of acute infection. Adoptive transfer studies have been used to study differentiation in this system however, relatively little work has investigated the phenotype of cells in the endogenous repertoire. We demonstrate that the extent of CD62L down-regulation is positively correlated with clone size in vivo, consistent with ision-linked differentiation of responding cells. Other features of the endogenous CD62L(hi) and CD62L(lo) repertoire are that the CD62L(lo) repertoire is less erse than the CD62L(hi) repertoire and represents a subset of clonotypes found in the CD62L(hi) repertoire. To test whether these observations are compatible with a mechanism of ision-linked differentiation, we developed a mathematical model, where there is a probability of CD62L down-regulation associated with cell ision. Comparison of model results with experimental data suggests that ision-linked differentiation provides a simple mechanism to explain the relationship between clone size and phenotype of CD8(+) T cells during acute infection.
Publisher: American Society for Microbiology
Date: 15-04-2000
DOI: 10.1128/JVI.74.8.3486-3493.2000
Abstract: Respiratory challenge of H-2 b mice with an H3N2 influenza A virus causes an acute, transient pneumonitis characterized by the massive infiltration of CD8 + T lymphocytes. The inflammatory process monitored by quantitative analysis of lymphocyte populations recovered by bronchoalveolar lavage is greatly enhanced by prior exposure to an H1N1 virus, with the recall of cross-reactive CD8 + -T-cell memory leading to more rapid clearance of the infection from the lungs. The predominant epitope recognized by the influenza virus-specific CD8 + set has long been thought to be a nucleoprotein (NP 366–374 ) presented by H-2D b (D b NP 366 ). This continues to be true for the secondary H3N2→H1N1 challenge but can no longer be considered the case for the primary response to either virus. Quantitative analysis based on intracellular staining for gamma interferon has shown that the polymerase 2 protein (PA 224–233 ) provides a previously undetected epitope (D b PA 224 ) that is at least as prominent as D b NP 366 during the first 10 days following primary exposure to either the H3N2 or H1N1 virus. The response to D b NP 366 seems to continue for longer, even when infectious virus can no longer be detected, but there is no obvious difference in the prevalence of memory T cells specific for D b NP 366 and D b PA 224 . The generalization that the magnitude of the functional memory T-cell pool is a direct consequence of the clonal burst size during the primary response may no longer be useful. Previous CD8 + -T-cell immunodominance heirarchies defined largely by cytotoxic T-lymphocyte assays may need to be revised.
Publisher: Elsevier
Date: 2007
Publisher: Proceedings of the National Academy of Sciences
Date: 03-08-1999
Abstract: To determine whether established CD8 + T cell memory to an epitope prominent during the replicative phase of a γ-herpesvirus infection protects against subsequent challenge, mice were primed with a recombinant vaccinia virus expressing the p56 peptide and then boosted by intranasal exposure to an influenza A virus incorporating p56 in the neuraminidase protein. Clonally expanded populations of functional, p56-specific CD8 + T cells were present at high frequency in both the lung and the lymphoid tissue 1 month later, immediately before respiratory challenge with γHV-68. This prime-and-boost regime led to a massive reduction of productive γHV-68 infection in the respiratory tract and, initially, to much lower levels of latency in both the regional lymph nodes and the spleen. The CD8 + T cell response to another epitope (p79) was diminished, there was less evidence of B cell activation, and the onset of the CD4 + T cell-dependent splenomegaly was delayed. Within 3–4 weeks of the γHV-68 challenge, however, the extent of latent infection in the lymph nodes and spleen was equivalent, and both groups developed the prominent infectious mononucleosis-like syndrome that is characteristic of this infection. The reverse protocol (influenza then vaccinia) seemed to be slightly less effective. Even though immune CD8 + T cells may be present at the time and site of virus challenge, establishing a high level of CD8 + T cell memory to lytic-phase epitopes alone does not protect against the longer-term consequences of this γHV infection.
Publisher: Elsevier BV
Date: 06-1995
Abstract: The relative prevalence of Sendai virus-specific CD4+ T helper precursors (Thp) has been assessed by limiting dilution analysis (LDA). Within 10 days after intranasal inoculation of C57BL/6 mice, Thp prevalence increased from < 1 in 10(5) to approximately 1 in 200 in CD4+ T-cell-enriched spleen and mediastinal lymph node populations. These frequencies remained elevated relative to naive animals, with the majority of the Thp recovered at 2-3 months after infection being found in the spleen. The "memory" Thp express an "activated" L-selectin-low, CD44-high, alpha 4-integrin-high phenotype, comparable to that described previously for CD8+ cytotoxic T lymphocyte precursors (CTLp) specific for Sendai virus. Background effects for the IL-2-based Thp analysis are, however, less predictable than those found previously for the 51Cr release CTLp LDA, as the extent of non-virus-specific lymphokine production varies. However, provided the analysis is appropriately controlled, the approach does allow useful comparisons between phenotypically different subsets of antigen-specific CD4+ T cells.
Publisher: The American Association of Immunologists
Date: 12-2014
Abstract: Although CD4+ T cell help (Th) is critical for inducing optimal B cell and CD8+ T cell responses, it remains unclear whether induction of CD4+ Th responses postinfection are also dependent on CD4+ T cell help. In this study, we show that activation of adoptively transferred Th cells during primary influenza A virus (IAV) infection enhances both the magnitude and functional breadth of endogenous primary IAV-specific CD4+ T cell responses. This enhancement was dependent on CD154-CD40–dependent dendritic cell licensing and resulted in a greater recall capacity of IAV-specific CD4+ and CD8+ T memory responses after heterologous IAV infection. These data suggest that engaging pre-existing CD4 responses at the time of priming may be a strategy for improving cellular immunity after vaccination.
Publisher: Mary Ann Liebert Inc
Date: 10-10-2002
DOI: 10.1089/088922202320567888
Abstract: High-resolution structures have revealed major pockets in the MHC class II peptide binding groove within a region designated Pl-P9. The region can accommodate 9-mer peptides, consistent with the observation that minimal core helper T (Th) cell determinants are usually eight or nine residues in size. Here we describe mouse Th cell hybridomas that are specific for a core peptide of only five residues (NPIIL) in the HIV envelope glycoprotein. Effective Th cell stimulation requires that these MHC class II Ia(b)-presented peptides contain amino acids flanking the minimal pentamer, but the flanking residues may be located on either the N or C terminus. To explain these findings, we suggest that mini-Th cell epitopes may effectively associate with MHC when only five (or possibly fewer) of the P1-P9 positions are filled. The remaining positions may be empty, or may be associated with a second, perhaps unrelated, peptide moiety.
Publisher: Rockefeller University Press
Date: 05-05-1997
Abstract: The murine γ-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62Llo) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2b) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vβ4+ phenotype. Interestingly, the Vβ4 dominance was also seen, to varying extents, in H-2k, H-2d, H-2u, and H-2q strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vβ4 bias of the T cells, the Vβ4+CD8+ expansion was absent in H-2IAb–deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody–depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vβ4+CD8+ T cells.
Publisher: Elsevier BV
Date: 03-1972
DOI: 10.1016/S0140-6736(72)90385-6
Abstract: Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-in idual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-05-2011
Abstract: Immunodominant T-cell responses are important for virus clearance. However, the identification of immunodominant T-cell peptide + HLA glycoprotein epitopes has been hindered by the extent of HLA polymorphism and the limitations of predictive algorithms. A simple, systematic approach has been used here to screen for immunodominant CD8 + T-cell specificities. The analysis targeted healthy HLA-A2 + donors to allow comparison with responses to the well-studied influenza matrix protein 1 epitope. Although influenza matrix protein 1 was consistently detected in all in idual s les in our study, the response to this epitope was only immunodominant in three of eight, whereas for the other five, prominent CD8 + T-cell responses tended to focus on various peptides from the influenza nucleoprotein that were not presented by HLA-A2. Importantly, with the four immunodominant T-cell epitopes identified here, only one would have been detected by the current prediction programs. The other three peptides would have been either considered too long or classified as not containing typical HLA binding motifs. Our data stress the importance of systematic analysis for discovering HLA-dependent, immunodominant CD8 + T-cell epitopes derived from viruses and tumors. Focusing on HLA-A2 and predictive algorithms may be too limiting as we seek to develop targeted immunotherapy and vaccine strategies that depend on T cell-mediated immunity.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-11-1998
Abstract: Dissection of the primary and secondary response to an influenza A virus established that the liver contains a substantial population of CD8 + T cells specific for the immunodominant epitope formed by H-2D b and the influenza virus nucleoprotein peptide fragment NP 366–374 (DbNP366). The numbers of CD8 + DbNP366 + cells in the liver reflected the magnitude of the inflammatory process in the pneumonic lung, though replication of this influenza virus is limited to the respiratory tract. Analysis of surface phenotypes indicated that the liver CD8 + DbNP366 + cells tended to be more “activated” than the set recovered from lymphoid tissue but generally less so than those from the lung. The distinguishing characteristic of the lymphocytes from the liver was that the prevalence of the CD8 + DbNP366 + set was always much higher than the percentage of CD8 + T cells that could be induced to synthesize interferon γ after short-term, in vitro stimulation with the NP 366–374 peptide, whereas these values were generally comparable for virus-specific CD8 + T cells recovered from other tissue sites. Also, the numbers of apoptotic CD8 + T cells were higher in the liver. The results overall are consistent with the idea that antigen-specific CD8 + T cells are destroyed in the liver during the control and resolution phases of this viral infection, though this destruction is not necessarily an immediate process.
Publisher: Elsevier BV
Date: 04-2009
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.VACCINE.2009.08.079
Abstract: Understanding CD8+ T cell responses generated by live virus vectors is critical for the rational design of next generation HIV CTL-based vaccines. We used recombinant influenza viruses expressing the HIV Env(311-320) peptide in the neuraminidase stalk to study response magnitude, cytokine production and repertoire ersity for the elicited CD8+ D(d)Env(311) CTL set. The insertion of the CD8+ D(d)Env(311) epitope into the NA stalk resulted in a decrease in viral fitness that was reflected in lower lung viral titres. While not affecting the magnitude of endogenous primary influenza-specific responses, the introduction of the D(d)Env(311) CD8+ T cell epitope altered the hierarchy of responses following secondary challenge. The CD8+ K(d)NP(147) response increased 9-fold in the spleen following secondary infection whereas the CD8+ D(d)Env(311) response increased 15-fold in the spleen. Moreover, this study is the first to describe narrowing of CD8+ TCR repertoire ersity in the context of an evolving secondary immune response against influenza A virus. Analysis of Vbeta bias for CD8+ D(d)Env(311) T cell responses showed a narrowing of CD8+ Vbeta8.1/8.2 D(d)Env(311) TCR repertoire ersity. This work further emphasizes the importance of understanding vaccine-induced CD8+ T cell responses.
Publisher: Springer Science and Business Media LLC
Date: 04-1998
DOI: 10.1038/33712
Abstract: DNA viruses have evolved elaborate mechanisms to overcome host antiviral defences. In adenovirus-infected cells, programmed cell death (apoptosis) induced by the cytokine tumour necrosis factor (TNF) is inhibited by several adenovirus-encoded proteins. Occupation of the cell-surface receptor Fas, a member of the TNF-receptor superfamily that is expressed on most cell types, triggers apoptosis of that cell. Here we show that the adenovirus RID (for receptor internalization and degradation) protein complex, which is an inhibitor of TNF-induced apoptosis, mediates internalization of cell-surface Fas and its destruction inside lysosomes within the cell. Fas has not previously been shown to be internalized and then degraded. RID also mediates internalization of the receptor for epidermal growth factor, but it does not affect the transferrin receptor or class I antigens of the major histocompatibility complex. Removal of Fas from the surface of adenovirus-infected cells expressing RID may allow infected cells to resist Fas-mediated cell death and thus promote their survival.
Publisher: Elsevier BV
Date: 08-1994
Publisher: Wiley
Date: 09-01-2007
Abstract: Influenza A viruses that circulate normally in the human population cause a debilitating, though generally transient, illness that is sometimes fatal, particularly in the elderly. Severe complications arising from pandemic influenza or the highly pathogenic avian H5N1 viruses are often associated with rapid, massive inflammatory cell infiltration, acute respiratory distress, reactive hemophagocytosis and multiple organ involvement. Histological and pathological indicators strongly suggest a key role for an excessive host response in mediating at least some of this pathology. Here, we review the current literature on how various effector arms of the immune system can act deleteriously to initiate or exacerbate pathological damage in this viral pneumonia. Generally, the same immunological factors mediating tissue damage during the anti-influenza immune response are also critical for efficient elimination of virus, thereby posing a significant challenge in the design of harmless yet effective therapeutic strategies for tackling influenza virus.
Publisher: Wiley
Date: 08-01-2008
Publisher: Wiley
Date: 06-2006
DOI: 10.1111/J.0105-2896.2006.00386.X
Abstract: The influenza A virus model of localized, transient respiratory infection provides a well-defined experimental system for dissecting the induction and maintenance of CD8+ T-cell memory. This review focuses on quantitative and qualitative aspects of the prominent D(b)NP366- and D(b)PA224-specific CD8+ T-cell responses in virus-infected B6 mice. The different virus-specific effector and memory sets are compared by phenotypic [CD62L, interleukin-7 receptor-alpha (IL-7Ralpha), and IL-15Rbeta expression] and functional [interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and IL-2 production] analyses. Most clonotypes [defined by T-cell receptor (TCR) CDR3beta sequence] generated during the acute phase of infection survive into memory, with those expressing the more consensus 'canonical' TCRs being the major contributors to the recall response. The extent of clonal expansion and the size of memory CD8+ T-cell populations has been characterized for mice challenged with either wildtype or mutant viruses, where broadly equivalent D(b)NP366 and D(b)PA224 expression was achieved by disabling the peptides in their native configuration, then expressing them in the viral neuraminidase protein. Combining the clonotypic and antigen dose analyses led to a somewhat mechanistic conclusion that the magnitude of any virus-specific CD8+ T-cell response will be a direct function of antigen dose and the size of the naïve or memory CD8+ T-cell precursor pool.
Publisher: Public Library of Science (PLoS)
Date: 23-02-2012
Publisher: Proceedings of the National Academy of Sciences
Date: 10-02-2006
Abstract: The ovalbumin 323–339 peptide that binds H2I-A b was engineered into the globular heads of hemagglutinin (H) molecules from serologically non-cross-reactive H1N1 and H3N2 influenza A viruses, the aim being to analyze recall CD4 + T cell responses in a virus-induced respiratory disease. Prime/challenge experiments with these H1ova and H3ova viruses in H2 b mice gave the predicted, ovalbumin-specific CD4 + T cell response but showed an unexpectedly enhanced, early expansion of viral epitope-specific CD8 + T cells in spleen and a greatly diminished inflammatory process in the virus-infected respiratory tract. At the same time, the primary antibody response to the H3N2 challenge virus was significantly reduced, an effect that has been associated with preexisting neutralizing antibody in other experimental systems. Analysis of serum from the H1ova-primed mice showed low-level binding to H3ova but not to the wild-type H3N2 virus. Experiments with CD4 + T cell-depleted and Ig −/− mice indicated that this cross-reactive Ig is indeed responsible for the modified pathogenesis after respiratory challenge. Furthermore, the effect does not seem to be virus-dose related, although it does require infection. These findings suggest intriguing possibilities for vaccination and, at the same time, emphasize that engineered modifications in viruses may have unintended immunological consequences.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2012
Publisher: Springer Science and Business Media LLC
Date: 06-1981
DOI: 10.1038/291432A0
Abstract: Bioassay-guided fractionation of the diethyl ether fraction of a water extract of Picea schrenkiana needles led to the isolation of the phenolic compound 3,4-dihydroxy- acetophenone (DHAP). The allelopathic effects of DHAP were evaluated under laboratory conditions on P. schrenkiana, rice (Oryza sativa L.), wheat (Triticum aestivum L.), radish (Raphanus sativus L.), lettuce (Latuca sativa L.), cucumber (Cucumis sativus L.) and mung bean (Phaseolus radiatus L.). DHAP significantly inhibited seed germination and seedling growth of P. schrenkiana at concentrations of 2.5 mM and 0.5 mM (p < 0.05). Soil analysis revealed that P. schrenkiana forest soils contained exceptionally high DHAP concentrations (mean = 0.51 ± 0.03 mg/g dry soil), sufficient to inhibit natural P. schrenkiana recruitment. DHAP also exhibited strong allelopathic potential. It significantly inhibited wheat and lettuce seed germination at concentrations of 1 mM and 0.5 mM (p < 0.05). The active compound also completely inhibited root growth of the six test species at high concentrations. Our results suggest a dual role of DHAP, both as an allelochemical and as an autotoxicant. The potential for a single plant needle-leached compound to influence both inter- and intra-specific interactions emphasized the complex effects that plant secondary metabolites might have on plant population and community structure.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-12-2008
Abstract: Understanding T cell immunodominance hierarchies is fundamental to the development of cellular-based vaccines and immunotherapy. A combination of influenza virus infection in C57BL/6J mice and reverse genetics is used here to dissect the role of T cell antigen receptor (TCR) repertoire in the immunodominant D b NP 366 CD8 + T cell response. Infection with an engineered virus (NPM6A) containing a single alanine (A) mutation at the critical p6 NP 366–374 residue induced a noncross-reactive CD8 + T cell response characterized by a novel, narrower TCR repertoire per in idual mouse that was nonetheless equivalent in magnitude to that generated after WT virus challenge. Although of lower overall avidity, the levels of both cytotoxic T lymphocyte activity and cytokine production were comparable with those seen for the native response. Importantly, the overdominance profile characteristic of secondary D b NP 366 -specific clonal expansions was retained for the NPM6A mutant. The primary determinants of immunodominance in this endogenous, non-TCR-transgenic model of viral immunity are thus independent of TCR repertoire composition and ersity. These findings both highlight the importance of effective antigen dose for T cell vaccination and/or immunotherapy and demonstrate the feasibility of priming the memory T cell compartment with engineered viruses to protect against commonly selected mutants viral (or tumor) escape mutants.
Publisher: Springer Science and Business Media LLC
Date: 07-1996
DOI: 10.1038/382171A0
Abstract: Signal transducers and activators of transcription (STATs) are activated by tyrosine phosphorylation in response to cytokines and mediate many of their functional responses. Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6,7). IL-12 is required for the T-cell-independent induction of the cytokine interferon (IFN)-gamma, a key step in the initial suppression of bacterial and parasitic infections. IL-12 is also important for the development of a Th1 response, which is critical for effective host defence against intracellular pathogens. To determine the function of Stat4 and its role in IL-12 signalling, we have produced mice that lack Stat4 by gene targeting. The mice were viable and fertile, with no detectable defects in haematopoiesis. However, all IL-12 functions tested were disrupted, including the induction of IFN-gamma, mitogenesis, enhancement of natural killer cytolytic function and Th1 differentiation.
Publisher: Wiley
Date: 11-2008
Abstract: Leishmaniasis is currently classified as category 1 disease, i.e. emerging and uncontrolled. Since the importance of persistent infection for maintaining an effective long-lasting protective response is controversial, the present study asks whether immunisation with non-persistent parasites leads to protection against Leishmania infection and to the recruitment of T cells of a specific phenotype. Our study shows that vaccination of susceptible BALB/c mice with live Leishmania major phosphomannomutase-deficient parasites, which are avirulent and non-persistent in vivo, leads to protection against infection. Immunisation with phosphomannomutase-deficient parasites neither leads to differences in IFN-gamma, IL-12, IL-4 production nor alters the expression of effector and memory markers, including CD62L, IL-7Ralpha and IL-2Ralpha, when compared with unvaccinated controls. Observed protection is due to the ability of vaccinated animals to suppress early IL-10 and IL-13 production and to recruit a higher number of antigen-experienced CD44hiCD4+ and CD44hiCD8+ T cells into draining LN following infection. Thus, expansion of T-cell numbers and their rapid recruitment to LN upon infection as well as the restriction of IL-13 and IL-10 production leading to high IFN-gamma/IL-10 ratio play an important role in protection against Leishmania affecting the outcome of the disease in favour of the host.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Peter Charles Doherty.